Abstract
Aging is an inevitable, physiological process of the human body, leading to deterioration in bodily function and increased susceptibility to various diseases. Effective endogenous therapeutic strategies for anti-aging and related diseases remain limited. Exercise confers multifaceted benefits to physical health by augmenting osteogenic and myogenic processes, enhancing cardiovascular and nervous system function, and attenuating chronic inflammation. Angiogenesis and lymphangiogenesis play pivotal roles in anti-aging, tissue repair, and immune response modulation, underscoring their potential as therapeutic targets for age-related diseases. Modulating angiogenic and lymphangiogenic pathways may provide a promising strategy for mitigating vascular decline and immune system dysfunction associated with aging. Exercise-induced endogenous angiogenesis and lymphangiogenesis can exert beneficial effects on physiological function, thereby representing a potential therapeutic paradigm for combating age-related decline and diseases. This review offers a thorough summary of the present knowledge regarding angiogenesis and lymphangiogenesis induced by exercise, encompassing the underlying mechanisms and the effects in different organs. In addition, it explores the potential of physical activity as a non-pharmacological intervention for anti-aging strategies and disease management, offering novel insights into the intersection of physical activity, aging, and disease progression.
Keywords: Exercise, Angiogenesis, Lymphangiogenesis, Aging, Disease
Introduction
Aging is linked to a decline in vascular homeostasis, marked by endothelial dysfunction, decreased capillary density, and impaired angiogenesis. These age-related vascular alterations compromise the efficient delivery of oxygen and nutrients to tissues.[1] As a result, this leads to an increased susceptibility to various diseases and disorders, including sarcopenia, dynapenia, cardiovascular diseases, disorders related to metabolism, and neoplastic diseases.[2,3,4] Likewise, the presence of chronic illness can expedite the process of biological aging and amplify the susceptibility to diseases.[5] Despite the current lack of approved anti-aging pharmaceuticals, ongoing research in this field is making significant advancements with the ultimate goal of identifying successful strategies to extend healthy aging and enhance the well-being of elderly people.[6]
Angiogenesis plays a critical role in promoting wound healing, tissue repair, and augmenting regional blood flow, particularly in the context of chronic ischemic disorders, such as cardiovascular and cerebrovascular diseases, neurodegenerative disorders, hypertension, and osteoporosis, where enhanced vascularization is essential for restoring tissue function and mitigating disease progression.[7] It enhances blood circulation by creating new vascular networks, ensuring the provision of sufficient oxygen and essential nutrients to injured tissues. Angiogenesis requires the synchronized collaboration of various cellular components and molecular signals. Vascular endothelial growth factor (VEGF) is a pivotal regulator of angiogenesis, promoting the proliferation of vascular endothelial cells. Elevated VEGF expression is a hallmark of the angiogenic response, particularly in ischemic tissues and organs, which are major contributors to morbidity and mortality in clinical settings. Elevated VEGF levels enhance capillary formation and increase vascular permeability, facilitating tissue repair and regeneration, which in turn mitigates ischemic damage and promotes vascular recovery.[8] Patients with diffuse stenosis-induced ischemia often face limited treatment options and suboptimal outcomes, despite advances in surgical and medical interventions. To address this unmet need, several innovative therapeutic strategies are being actively investigated to promote angiogenesis, including cellular transplantation,[9] gene therapy,[10] and cytokine-based treatments,[11] which hold promise for enhancing vascular regeneration and improving tissue perfusion and mitigating ischemia-related damage. However, the inconsistent experimental results have hindered the clinical translation of stem cell transplantation, gene therapy, and cytokine-based interventions.
The biological process of lymphangiogenesis is essential for development, tissue regeneration, immune system function, and restructuring of the lymphatic system in disease states.[12] Lymphangiogenesis plays a crucial role in wound healing and tissue repair by augmenting immune function and nutrient transport, thereby expediting the recovery of damaged tissues.[13] In addition, in the context of cardiovascular and metabolic disorders, lymphangiogenesis contributes to enhanced lymphatic vessel function, improved fluid balance, and regulated lipid metabolism, ultimately leading to amelioration of disease pathology.[14] Lymphangiogenesis may inhibit tumor metastasis for tumor therapy, as it activates immune cells and enhances the effectiveness of immunotherapy.[15] Thus, regulating lymphangiogenesis and its function may provide new strategies and targets for treating diseases related to lymphatic vessel dysfunction, such as inflammatory disease.[16] However, the mechanism underlying the promotion of lymphangiogenesis in health promotion and disease interventions remains unclear.
A growing body of evidence suggests that exercise-induced endogenous angiogenesis and lymphangiogenesis play a crucial role in maintaining overall health. Exercise-mediated angiogenesis involves upregulation of VEGF, which improves blood supply and promotes endothelial cell renewal, eventually rebuilding the new vascular network to establish collateral circulation.[17] Exercise triggers various signaling, such as peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), adenosine, VEGF, and sirtuin 1 (SIRT1) in skeletal muscles, thereby leading to an increase in the size of muscles and promoting muscular angiogenesis. These modifications were linked to the enhancement of glucose metabolism, angiogenesis, and mitochondrial function in the muscle.[18,19] High-intensity interval training (HIIT) resulted in a significant increase in vascular density and cardiac performance in rats, with improvements observed in both the contraction and relaxation functions of the heart.[20] Furthermore, aerobic-interval training has been shown to effectively inhibit the remodeling of adipose tissue induced by a high-fat diet, by stimulating an increase in capillary density and promoting macrophage polarization.[21] Moreover, exercise has been demonstrated to promote neovascularization in the motor cortex of running rats, leading to increased capillary formation and vascular remodeling in the brain, suggesting that physical activity positively influences the growth and adaptability of cerebral blood vessels.[22] Treadmill running in rats significantly enhanced lymphatic drainage and reduced edema, suggesting a pivotal role in facilitating lymphatic vessel regeneration and restoring lymphatic function.[23] These findings highlight the potential benefits of exercise in various organs by increasing the number of blood vessels and lymph vessels.
This review synthesizes recent advancements and potential mechanisms of exercise-induced angiogenesis and lymphangiogenesis in various organs, with a focus on their roles in combating aging and disease. Exercise-induced angiogenesis and lymphangiogenesis have the potential to promote overall health and combat aging and diseases, offering new targets for anti-aging and disease therapies.
Effects of Exercise in Anti-Aging
Numerous studies have demonstrated that exercise has a profound impact on aging-related outcomes, reducing chronic inflammation, enhancing physical function, and increasing lifespan, ultimately promoting healthy aging.[24,25] Exercise has been found to decrease the accumulation of senescent cells in multiple organs, including the heart, brain, liver, and muscle, effectively contributing to the maintenance of a more youthful physiological state.[26] Endothelial dysfunction is one of the characteristics of vascular aging. Exercise improved endothelial function by activating endothelial nitric oxide synthase (eNOS) in the coronary artery endothelium, and increased the availability of nitric oxide (NO) derived from cardiac endothelial cells by regulating mitochondrial respiration, inhibiting β1-adrenergic receptor-induced contractility enhancement, and inducing cyclic guanosine monophosphate-dependent relaxation.[27,28] Exercise-induced production of fibronectin type III domain-containing protein 5/irisin has been shown to be transported to blood vessels via exosomes, where it inhibits vascular aging.[29] The increased production of reactive oxygen species (ROS) in the aging heart led to mitochondrial damage and impaired cardiac function. Regular exercise has been shown to mitigate ROS levels and enhance antioxidant capacity by upregulating the expression of antioxidant enzymes, such as superoxide dismutase and glutathione peroxidase.[30] In addition, exercise had a multifaceted beneficial impact on the aged mouse heart, characterized by increased myocardial oxygen consumption, enhanced glucose and fatty acid uptake, elevated adenosine triphosphate (ATP) production, and improved autophagic flux. It promoted the clearance of protein aggregates and improved contractile performance, collectively contributing to improved cardiac function in aged mice.[31,32,33] Resistance training has been shown to stimulate a moderate increase in muscle protein synthesis, facilitating muscle growth and development. This, in turn, enhances muscle strength in elderly individuals, particularly those who are frail.[34] Regular exercise delayed muscle aging by activating the nicotinamide adenine dinucleotide/SIRT1 pathway. It increased muscle fiber size, muscle mass, and improved muscle function, while reduced age-related muscle strength decline.[35] Exercise-induced increased expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in skeletal muscle leads to an increase in ROS, thereby alleviating the decline in insulin sensitivity associated with aging and obesity, and preventing the impact of aging at the metabolic level.[36] Aerobic exercise alleviates age-related cognitive decline and neurodegeneration, potentially preventing Alzheimer’s disease by modulating microglial activity and neuroplasticity.[37] Key mechanisms include insulin-like growth factor-1 (IGF-1)/VEGF upregulation to suppress microglial activation, enhance neurogenesis/angiogenesis, improve cerebral insulin signaling, increase blood flow, and reduce β-amyloid accumulation.[38] These adaptations collectively preserve brain health and cognitive function during aging. In a D-galactose-induced aging rat model, swimming significantly reduced aging markers and pro-inflammatory cytokines in the liver, thereby rejuvenating it.[39] Another study showed that exercise activated adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) and unc-51-like autophagy activating kinase 1 through muscle-secreted fibroblast growth factor 21 to promote autophagy and lipophagy in the liver, thereby improving non-alcoholic fatty liver disease and delaying liver aging.[40] Exercise has been shown to counteract skin aging by protecting the extracellular matrix of the dermis, thereby preserving skin elasticity and maintaining the structural integrity of the upper dermal layer. In addition, it promotes blood circulation, reduces the expression of factors, such as chemokine (C-C motif) ligand 28 (CCL28) and N, N-dimethylglycine, and decreases the levels of pro-inflammatory factors, including interleukin 5 (IL-5), which were closely linked to the skin aging process.[41] By mitigating these age-related changes, exercise contributes to improved skin health and appearance. In general, regular exercise has been widely recognized as a key factor in promoting healthy aging and rejuvenation. This review highlights the critical role of exercise-induced angiogenesis and lymphangiogenesis in various organs and tissues and their collective impact on mitigating the effects of aging and promoting overall health.
Exercise-Induced Angiogenesis and Lymphangiogenesis in Multiple Organs: Anti-Aging and Protection Against Disease Effects
Blood vessel
Exercise induces proangiogenic potential in circulation
Exercise has the potential to stimulate angiogenesis by activating various signaling pathways, including growth factors, proteins, angiogenic cells, and specific microRNAs. It is commonly recognized that hypoxia is one of the most important factors to induce neovascularization.[42] A comparative study explored the impact of low oxygen on the levels of VEGF and matrix metalloproteinase-9 (MMP-9) in male subjects following acute exercise. The results demonstrated that VEGF levels were significantly increased 10 min post-exercise in response to hypoxia. In addition, MMP-9 level was elevated 240 min after exercise at a higher altitude.[43] Both blood-flow-restriction exercises (BFRE) and conventional training positively impacted endothelial function and angiogenesis in healthy participants.[44] Post-exercise analysis revealed significant elevations in serum CD34 protein and platelet endothelial cell adhesion molecule-1 (PECAM-1) level. Notably, the BFRE group exhibited higher levels of vascular endothelial growth factor receptor 2 (VEGFR-2) in comparison to the group that underwent no BFRE. High expressions of VEGFR-2 and CD34 play a role in stimulating angiogenesis and vascular development.[45] A 6-week repeated sprint exercise training program under hypoxic conditions yielded substantial improvements in aerobic performance and peak oxygen uptake (VO2peak). Notably, the study revealed that repeated sprint training under hypoxic conditions led to a significant increase in serum concentrations of hypoxia-inducible factor-1 (HIF-1α) and VEGF.[46]
Endothelial progenitor cells (EPCs) are reported as precursor cells of vascular endothelial cells, which can be mobilized from bone marrow to peripheral blood to participate in the repair of injured blood vessels under the stimulation of physiological or pathological conditions.[47,48] Some studies found EPCs had the capacity to aid in endothelial repair, enhance vascularization, and rejuvenate endothelial function.[49] A recent review summarized methods for characterizing EPCs, such as positive expression of endothelial cell markers (including von Willebrand Factor, tyrosine kinase with Ig and EGF homology domain 2 (Tie2), kinase insert domain protein receptor, and CD31) and stem cell markers like CD34 or CD133.[50] It is worth noting that there is still controversy about the formation of vascular endothelial cells by stem cells or other types of cells through cell differentiation or transdifferentiation.[51] Acute resistance exercise sessions of varying intensities elicited transient elevation of CD45dim/KDR+/CD34+ EPCs, VEGF, erythropoietin (EPO), as well as HIF-1α in healthy premenstrual women.[52] Another separate study demonstrated that a single session of sprint interval exercise led to a notable rise in circulating CD34+ stem cells and immune cells, with no changes observed in the non-exercise people.[53] Both sprint interval training and sprint continuous training led to enhancements in cardiorespiratory health indicators and an increase in circulating CD34+ cell counts among young, healthy women. In addition, 12-week bicycle ergometer training of male athletes increased CD34+ stem cells and circulating progenitor cells.[54] A recent investigation identified a subset of peripheral blood mononuclear cells (PBMCs) called CD62E+ through experiments on acute endurance exercise in healthy young individuals. These cells were found to promote angiogenesis more significantly after exercise compared to CD31+ and CD34+ PMBCs.[55] In addition, CD62E+ cells were also found to be capable of inducing the expression of angiogenic genes in vitro. These studies indicated that exercise had an impact on the number of circulating angiogenic cells and could potentially support vascular growth and maintenance.
Exercise-induced dynamic regulation of circulating microRNAs has been shown to regulate a variety of physiological functions, such as angiogenesis and tissue repair. A study conducted on basketball players over a 3-month season found that regular training and match play led to temporal changes in the circulating levels of specific microRNAs, namely microRNA-208b (miR-208b) and miR-221.[56] Notably, miR-221/miR-222 have been implicated in regulating vascular generation activity of stem cell factor, influencing erythropoiesis and reproduction of blood vessels in both normal and abnormal situations.[57]
Exercise counteracts vascular aging
Aging is associated with elevated oxidative stress and low-grade systemic inflammation, both of which play crucial roles in arterial stiffening. In addition, aging is marked by the progressive deterioration of endothelial cell function, leading to endothelial dysfunction and consequent vascular system damage.[58,59] Furthermore, vascular aging is a complex process characterized by a multitude of factors, including the disruption of proteostasis, genomic instability, cell cycle dysregulation, altered calcium signaling, hyperuricemia, increased apoptosis and necroptosis, and epigenetic changes. These factors have been extensively investigated in numerous studies, providing valuable insights into the underlying mechanisms of vascular aging.[60,61] VEGF plays a vital role in maintaining the homeostasis and functionality of various organs. A deficiency in VEGF has been linked to numerous age-related organ dysfunctions, including muscle,[62] kidney,[63] liver,[64] brain,[65] and gastric mucosa impairments.[66] Interestingly, testosterone therapy in older individuals has been shown to enhance angiogenesis and promote tissue regeneration through VEGF-dependent mechanisms.[67] Proper supplementation of VEGF has been found to promote the rejuvenation and regeneration of muscles, liver, bones, and other organs, while maintaining vascular regeneration and permeability. This, in turn, can significantly mitigate age-related functional decline. Moreover, VEGF has been shown to enhance the health of aged mice, highlighting its potential as a therapeutic agent for promoting healthy aging.[68,69] Treatment with VEGF and vascular permeability factor has the potential to delay the aging process of vascular endothelial cells and enhance their proliferative capacity.[70] These findings suggest that VEGF has important potential to combat cellular and organ aging. Some studies have demonstrated that exercise rejuvenates aging blood vessels and enhances endothelial function through inducing angiogenesis. A study has shown that a 12-week regimen of treadmill running had a significant impact on CD34+/KDR+ or KDR+/CD133+ EPCs, particularly among young (26 ± 3 years old) and older (67 ± 3 years old). Notably, the older men exhibited an enhanced capacity for endothelial regeneration following the training period, which was correlated with improvement in intracellular signaling, particularly the activation of the C-X-C chemokine receptor type 4 (CXCR4). It was also found that Janus kinase-2 (JAK-2), as the downstream target of CXCR4, was co-regulated in this process.[71] Regular physical activity has been recommended as a potential strategy to mitigate the age-related decline in endothelial repair capacity and protect against blood vessel damage. A meta-analysis study examined alterations in angiogenesis markers in the bloodstream of older adults (≥50 years) before and after exercise.[72] The analysis of numerous articles revealed that exercise can consistently increase the concentration of VEGF. This suggests that exercise has a beneficial impact on promoting the formation of new blood vessels in older individuals, which can contribute to maintaining cardiovascular health and overall well-being for the elderly.
Exercise protects against vascular diseases
Microvessel rarefaction (MVR), a common occurrence in individuals with high blood pressure, is characterized by a decrease in the density and quantity of small blood vessels. This procedure may result in reduced circulation of blood and decreased supply of oxygen to different organs, ultimately contributing to microvascular damage.[73] A study has shown that aerobic exercise could result in enhancements in MVR for individuals with hypertension. The improvement was intricately linked to the recovery of damaged ability to form tubes and the late CD31+/KDR+/Tie-2+ EPCs’ capacity for creating new blood vessels. Furthermore, the 134 essential hypertensive patients who engaged in cycle ergometer exercise exhibited potential for effectively alleviating MVR in hypertension by restoring the ability of late EPCs through Notch1/protein kinase B (Akt)/eNOS pathway.[74] Another study has shown that hypertensive individuals who underwent an aerobic cycle ergometer experienced a reinforcement in the quantity and density of capillaries in skeletal muscle, as well as improvements in capillary ultrastructure.[75] The aerobic exercise may improve diffusion conditions in individuals with essential hypertension by increasing capillary density. Thrombus is a small blood clot that forms on the inner surface of the vascular system, typically resulting from vascular damage, blood hypercoagulability, or vascular stenosis. Angiogenesis, reduced inflammation, and enhanced collagen production facilitate the formation of fresh vascular networks, alleviate swelling or pain associated with thrombus formation, and contribute to the breakdown of the thrombus, ultimately enabling its dissolution.[76] A study has shown that upregulation of SIRT1 improved functionality of Sca-1+/VEGFR-2+ EPCs, including their migration and proliferation capabilities, facilitating angiogenesis.[77] As a result, SIRT1 might promote angiogenesis by increasing VEGF and reducing inflammation, which is important for resolving blood clots and reopening blocked blood vessels.[78] Mice that performed climbing ladder exercise for 14 and 28 days showed elevated levels of SIRT1 and VEGF in the vicinity of the blood clot, along with an increased density of small blood vessels in that specific area.[79] This implied that exercise could impact the process of thrombolysis and revascularization through the modulation of SIRT1.
Heart
Exercise-induced cardiac angiogenesis/lymphangiogenesis
Growing cardiomyocytes require adequate vascular support to ensure they receive sufficient nutrients and oxygen, thereby maintaining their metabolic demands and functional capacity during development. These vessels undergo further differentiation and acquire the specific characteristics of a coronary artery or vein.[80,81] After birth, the myocardial vascular plexus undergoes expansion through both angiogenesis and physiological neoangiogenesis.[82] Angiogenesis plays a pivotal role in myocardial repair following injury. The formation of new blood vessels in the ischemic heart stimulates the growth of microvasculature within the ischemic myocardium, facilitating self-bypass and establishing collateral circulation. This process enhances blood flow to the ischemic region, thereby promoting myocardial recovery. In the early stages of myocardial ischemia or infarction, an increase in capillary density is observed. Necrotic cardiomyocytes trigger the expression of various cytokines and growth factors, leading to the development of new vascular pathways and ultimately improving myocardial perfusion.[83] Cardiac lymphatic vessels emerge during embryonic development and continue to undergo structural and functional maturation. Both venous and non-venous origins contribute to the formation of the cardiac lymphatic endothelium. Postnatal cardiac lymphangiogenesis plays a crucial role in maintaining normal cardiac function under homeostatic conditions and facilitating cardiac repair following injury, as summarized in a review.[84] This suggests that following injury to the adult heart, the lymphatic vessels of the heart undergo growth and sprouting to eliminate edema and enhance immune cell infiltration, thereby facilitating cardiac repair and regeneration.
Prior studies showed that both aerobic and anaerobic exercise can trigger a significant increase in HIF-1α and VEGF levels in the myocardium of exercised rats. Temporal analysis revealed a rapid peak in HIF-1α expression on day 1 in the aerobic exercise group, whereas the anaerobic exercise group demonstrated a delayed yet sustained elevation.[85] Treadmill running resulted in enhanced angiogenesis, as evidenced by increased capillary density. In addition, this exercise regimen was associated with dynamic changes in extracellular matrix remodeling, characterized by decreased MMP-2 activity and increased MMP-9 activity at the onset of training.[86] Exercise-induced angiogenesis and vascular function enhancement are associated with modulations in enzyme activities, including MMPs and dimethylarginine dimethylaminohydrolase 1 (DDAH1). DDAH1, mainly found in endothelial cells and myocardium, is essential for controlling vascular function. Notably, DDAH1 has been shown to play a regulatory role in myocardial angiogenesis during physical activity.[87] In support of this, a study found that eight weeks of swimming exercise in mice resulted in a significant elevation of DDAH1 protein, whereas sedentary mice exhibited no change. Furthermore, swimming exercise induced significant increases in VEGF and caveolin-1 levels, collectively indicating the promotion of cardiac angiogenesis.[88] These results also indicate that DDAH1 promotes the development of blood vessels in the heart by regulating the related RAS viral (r-ras) oncogene homolog (R-Ras)/Akt/glycogen synthase kinase 3β (GSK3β) signaling pathway. Exercise has been shown to promote cardiac angiogenesis by upregulating the expression of VEGF and miR-126. A study in rats demonstrated that both moderate and high-volume swimming exercise for 10 weeks led to increased capillarization, as evidenced by a higher ratio of capillary-to-fiber, as well as elevated VEGF protein expression and increased miR-126 expression in cardiac tissue, highlighting the angiogenic benefits of exercise on the heart.[89] High-volume training further augmented the manifestation of angiogenic biomarkers. Activating mitogen-activated protein kinase (MAPK) played an important role in promoting angiogenesis. Another signaling pathway, phosphoinositol-3-kinase (PI3K)/Akt/eNOS, was also involved in this process. Following a six-week treatment regimen, garlic and voluntary exercise synergistically increased levels of cardiac miR-126 and miR-210, as confirmed by enhanced CD31 expression. Notably, both garlic and voluntary exercise, administered individually or in combination, significantly upregulated the expression of these angiogenic microRNAs in the myocardium, thereby facilitating angiogenic adaptation.[90] Exercise has been shown to have multifaceted benefits, which include improvement in cardiovascular fitness and muscle strength, promoting the growth of new lymphatic vessels, ultimately contributing to better overall health.[91] It has been shown that a 3-week swimming regimen induces upregulation of VEGFR-3, which was associated with the promotion of lymphatic vessel growth, as well as podoplanin (Pdpn) and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) in cardiac tissues of mice. Study demonstrates that selective pharmacological inhibition of VEGFR-3 signaling using SAR131675 mitigates exercise-induced cardiomyocyte hypertrophy and proliferation.[92] It suggested that the process was critically influenced by VEGFR-3-dependent lymphangiogenesis. The lymphatic system is involved in maintaining the equilibrium of fluid levels within tissues and assisting in the recovery of inflamed tissues. Furthermore, alterations in the arrangement and structure of lymphatic channels within muscle tissue have been observed after muscle injury, with significant differences in their quantity and size during the recovery phase, especially on day 4 post-injury, indicating regeneration and improvement.[93] A six-week study involving rats subjected to downhill running revealed a paradoxical effect on lymphatic vessel density, with a decrease observed in skeletal muscles and a significant increase in cardiac tissue.[94] The exercise-induced elevation in cardiac lymphatic vessel density was accompanied by increased expression of extracellular matrix components specific to lymphatic vessels, including vascular endothelial growth factor C (VEGF-C), vascular endothelial growth factor D (VEGF-D), LYVE-1, and Pdpn. In addition, the study found significant increases in caveolin-1 and VEGFR-3 expression in the myocardium following exercise. In contrast, skeletal muscles subjected to eccentric stress exhibited increased inflammation. The discrepancy may result from tissue-specific responses and species differences. The magnitude of mechanical stress likely determines distinct extracellular matrix adaptations in lymphatic vessels of skeletal muscle and myocardium. In cardiac tissue, myocardial contractions strongly stimulate lymphangiogenesis, whereas in skeletal muscle, this contraction pattern may induce excessive mechanical stress, potentially reducing lymphatic vessel density (LVD). Moreover, myocardial contraction is beneficial for enhancing the cardiac function of patients with cardiovascular diseases.[95] Furthermore, no changes in LVD of skeletal muscle were found after chronic training in the mouse model, while a decrease in LVD of human skeletal muscle was observed after 45 days of moderate cycling exercise. Both types of muscle contraction induce different lymphangiogenesis and LVD adaptations, accompanied by inducing alterations in the lymphangiocapillary-specific microenvironment, thereby influencing lymphangiogenesis.[96]
Exercise counteracts cardiac aging
Aging in the heart is generally characterized by pathological myocardial remodeling, cardiac hypertrophy, arrhythmias, and microcirculatory dysfunction. Cardiac function progressively declines with age, as evidenced by increased workload, diminished pump efficiency, and reduced myocardial compliance resulting from inadequate coronary perfusion and oxygenation.[97] The mechanism of cardiac aging is associated with a multitude of factors, including oxidative stress, mitochondrial dysfunction, telomere damage, noncoding RNAs, dysregulation of IGF-1/mammalian target of rapamycin (mTOR) signaling, and metabolite imbalance.[98,99,100] With advancing age, the cardiovascular system undergoes persistent mechanical and metabolic strain, leading to an increased risk of cellular and organ impairment. This is accompanied by profound structural and functional remodeling in cardiac tissues, vascular networks, and microcirculatory systems.[101] Aging impairs the vascular regenerative capacity and endothelial cell function, thereby exacerbating susceptibility to cardiovascular disease.[102,103]
Exercise exhibits anti-aging properties by enhancing cardiac function, promoting efficient removal of waste products, and mitigating cellular senescence.[104] During a 16-week period, rats that engaged in treadmill running showed an exercise-induced rise in eNOS and heat shock protein 70 (HSP70) levels in the left ventricle following ischemia-reperfusion. This intervention showed promise in improving the recovery of contractile function and resistance to ischemia-reperfusion in aged rats (20–24 months old), thereby mitigating age-related decline in cardiovascular function.[105] Trainings that incorporate both aerobic and resistance exercise over an 8-week period have been demonstrated to significantly enhance the angiogenesis in cardiac tissue of aged rats (20–24 months old). This enhancement was attributed to improvement in aerobic endurance and elevated levels of specific proteins associated with vasculature formation, including eNOS, VEGF, and HIF-1α.[106] A study examined the cardiac lymphatic system in aged (20-month-old) and young (2-month-old) mice. Compared to younger counterparts, aged hearts exhibited diminished lymphatic vessel density, pronounced vessel dilation, and elevated inflammatory and fibrotic responses in peri-lymphatic regions. However, following an 8-week voluntary running regimen, aged mice displayed significant amelioration of lymphatic remodeling, characterized by reduced vessel dilation, enhanced lymphatic density and branching, and decreased peri-lymphatic inflammation and fibrosis. These results demonstrate that aging impairs cardiac lymphatic function, while aerobic exercise promotes structural and functional restoration in the aged lymphatic vasculature.[107]
Exercise protects against cardiovascular diseases
Reperfusion therapy, which aims to restore blood flow to the heart tissue, is a highly effective treatment for acute myocardial infarction (MI) in clinical settings. By promptly reestablishing circulation, reperfusion therapy helps to minimize tissue damage and improve outcomes following a period of ischemia or reduced blood flow. However, the oxidative stress, inflammatory cell infiltration, and calcium overload caused by reperfusion can induce myocardial ischemia-reperfusion injury (I/RI) as well as microvascular impairment.[108] Combining berberine supplementation with HIIT can have a preconditioning effect on the heart, protecting it from MI as observed after 1 week post-MI and lasted for 8 weeks running on a treadmill.[109] It has been observed that these interventions alone could protect the heart from damage through stimulating angiogenesis one week after I/RI by increasing the levels of angiogenic factors like VEGF and fibroblast growth factor-2 (FGF-2) and decreasing the levels of thrombospondin-1 (TSP-1) and caspase-3 protein, thus inhibiting cardiomyocyte apoptosis.[110] Studies in MI models have demonstrated that aerobic exercise exerts beneficial effects on cardiac function.[111,112] Exercise has been shown to upregulate follistatin-like protein 1 (FSTL1) and VEGF levels, activate transforming growth factor-β (TGF-β)/Smad2/3 and PI3K/eNOS pathways, as well as decrease the expression of myocardial fibrosis-associated microRNAs (such as miR-15a and miR-146a), ultimately promoting angiogenesis and cardiac repair.[113,114,115] Studies indicate that exercise-induced upregulation of kinin B1 and B2 receptors in MI rats is crucial for promoting angiogenesis, as receptor antagonism abrogates this pro-angiogenic effect. In addition, antagonist treatment inhibited the increased levels of VEGF and eNOS in response to exercise.[116] Another study also suggested that kallikrein-kinin system have an important function in promoting myocardial angiogenesis.[117] Heart failure (HF) is a complex and multifaceted condition characterized by structural and functional disruptions to the heart, ultimately leading to its inability to supply sufficient oxygen to meet the metabolic demands of the tissues.[118] In a pathologically hypertrophic myocardium, the induction of angiogenesis is crucial to accommodate the increased metabolic demands, thereby preventing the progression to HF. Angiogenic signaling pathways can be activated as a compensatory response to ischemia, ensuring adequate oxygenation and perfusion of affected tissues, thereby maintaining coronary circulation and protecting against cardiac dysfunction and HF.[119] Study has shown that combination of caloric restriction and exercise yields beneficial effects on cardiovascular disease treatment in rats. In an isoproterenol-induced HF model, food restriction with the exercise reduced plasma levels of oxidative stress (malondialdehyde, pro-oxidant/anti-oxidant balance) and promoted angiogenesis in left ventricle through activating HIF-1α, thus elevating levels of VEGF.[120] Both HIIT and HIIT combined with strength training (including leg extensions and leg curls) led to improvements in diastolic function in male patients with stable HF. Furthermore, both exercise led to an upregulation of signals that promoted angiogenesis (angiopoeitin-2, VEGFR-2, and VEGF) in skeletal muscle and HIF-1α in HF patients.[121] After 8 weeks of exercise, VEGF levels were elevated, and there was an enhancement in citric acid synthetase activity and exercise capacity among patients with HF.[122] Studies have shown that only patients who participated in combined exercise training demonstrated increased capillarization, suggesting that the inclusion of resistance training in a cardiac rehabilitation regimen could potentially not only stimulate muscle development, but also improve muscle capillary density.[123] In addition, in heart failure with reduced ejection fraction (HFrEF) patients, there was a notable decrease in plasma levels of miR-191 directly following a cardiopulmonary exercise assessment, which corresponded to an improvement in arterial stiffness. Conversely, alterations in miR-23a were associated with improved vascular function.[124] In HFrEF patients, knee-extensor exercise resulted in significant improvements in leg vascular resistance and noradrenaline spillover. In addition, there was a significant increase in the growth of muscle fibers, capillarization, a higher proportion of type I fibers, and enhanced mitochondrial volume after the training period.[125] These findings indicated that HFrEF patients exhibited both structural and functional adaptability as well as appropriate angiogenic signaling within their muscles.
Muscle
Exercise-induced muscular angiogenesis
Muscle injury is characterized by damage to the vascular network, leading to a depletion of satellite cells, which in turn adversely affects endothelial cells and compromises the integrity of the entire vascular structure.[126] A reduction in the number of capillaries within skeletal muscle leads to decreased efficiency in nutrient transport, ultimately resulting in impaired muscle function.[127] Angiogenesis plays a crucial role in the regeneration and reconstruction of tissues following skeletal muscle injury, often occurring concurrently with myogenesis. The establishment of an adequate vascular network is essential for preventing fibrosis and ensuring optimal muscle fiber growth and development. Through a synergistic interaction, endothelial cells and myogenic precursors work together to enhance blood flow, maintain capillary wall integrity, regulate sarcomere length, and ultimately facilitate the efficient repair of damaged muscles.[128] Lymphatic vessels represent an essential component of the musculoskeletal system, serving a vital function in the clearance of waste products and metabolites from muscle tissues. Moreover, they facilitate the removal of excess water and electrolytes, thereby maintaining fluid homeostasis within the muscle environment.[129] In response to muscle injury, lymphatic vessels undergo significant structural and functional changes, necessitating the formation of new lymphatic vessels to restore function and maintain tissue homeostasis in ischemic tissues. Lymphatic endothelial cells play a crucial role in this process by secreting a diverse array of factors, including cytokines and chemokines, which modulate the local tissue microenvironment.[130,131] Notably, studies have shown that VEGF-C, secreted by CD11b+ cells, induces lymphangiogenesis and promotes blood flow recovery in a mouse model of hind limb ischemia.[132] These findings suggest that the rebuilding of the lymphatic network is a critical component of muscle repair, highlighting the importance of lymphangiogenesis in tissue regeneration.
The capillarization of skeletal muscle has the potential to impact both muscle fiber number and size. Older individuals were found to require an increase in leg blood flow and leg oxygen uptake.[133] Increased development of capillaries facilitates enhanced transfer of gases and metabolites between the bloodstream and muscle tissue, leading to higher maximum oxygen uptake and oxidative ability.[134] The wide-ranging physiological impacts of exercise on an organism are extensive and have a substantial impact on promoting angiogenesis and enhancing muscle functionality.[135] Forkhead box O3 (FoxO3a) has been reported to suppress the senescence process in endothelial cells by modulating the antioxidant/ROS/p27Kip1 pathways as well as p53/p21-dependent pathways.[136,137] Exercise has been demonstrated to have a notable effect on the messenger RNA (mRNA) expression levels in skeletal muscle, such as of HIF-1α, VEGF, and PGC-1α. In addition, it results in a reduction of mRNA expressions of muscle RING-finger 1 (MuRF-1), FoxO3a, and atrogin-1.[138] These adaptive changes ultimately enhance muscle oxygenation and metabolic efficiency. A study involving mice subjected to 6 weeks of treadmill running under hypoxic conditions revealed that β-adrenergic signaling was activated, leading to a significant increase in PGC-1α expression in the gastrocnemius muscle. This exercise activated the estrogen-related receptor α (ERRα)/VEGF axis and stimulated angiogenesis in the muscles.Furthermore, hypoxic exercise enhanced the biogenesis and function of mitochondria in muscle cells biogenesis and function, as evidenced by increased citrate synthase activity, ATP content, and synthase activity, ultimately enhancing mitochondrial turnover and muscle metabolic efficiency. A separate investigation involving mice subjected to 6 weeks of treadmill exercise and/or hypoxia yielded notable findings. The results showed a significant enhancement in ATP storage and synthesis, attributed to increased p38 MAPK activities and elevated PGC-1α expression. This exercise regimen effectively stimulated signaling pathways involved in mitochondrial biogenesis. Furthermore, the study revealed upregulation of VEGF in skeletal muscle, accompanied by an increased number of CD31+ cells, indicating enhanced angiogenic activity and promoting the formation of new blood vessels to support the increased energy demands of exercising muscle.[140] Elevated HIF-1α, VEGFR-2, and eNOS gene expressions were observed in addition to a rise in the number of capillaries within skeletal muscles following 12 weeks of high-intensity training.[141] Resistance exercise in low-oxygen environments enhanced muscle vascularization, circulation, and oxygen supply by promoting new blood vessel growth through increased VEGF expression.[142] It has been reported that exercise in a low oxygen environment upregulated VEGF levels.[143] In addition, Andrzejewski et al[144] found that massage therapy combined with exercise significantly boosted vascular growth factors in rat tendons. Rats engaging in physical activity on a running course, followed by 5-min massages on each rear leg, exhibited increased expression of vascular endothelial growth factor A (VEGF-A) mRNA and CD34 mRNA.[144] A 60-day exercise study on young largemouth bass revealed that physical activity effectively stimulated angiogenesis by increasing the expression of genes such as VEGF-A and its receptor VEGFR-2 in the liver and muscles. This led to a significant increase in blood vessel formation, ultimately resulting in enhanced muscle mass.[145] Furthermore, exercise was found to upregulate genes involved in growth, including ribosomal protein S6 kinase β1 and IGF-1. Similarly, treadmill exercise in rats increased the expression of muscle growth factor genes, including mTOR, VEGF, and VEGFR-1 mRNA.[146] This led to increased muscle growth and metabolism, as well as improvements in body weight and lipid metabolism.
The immediate regulation of blood vessel size, facilitated by NO-related signaling molecules, is crucial in active tissues such as skeletal muscles during prolonged exercise. The nitric oxide synthase/nitric oxide (NOS/NO) system plays a crucial role in stimulating angiogenesis in muscle tissue, as it helps to enhance energy supply by promoting the formation of new blood vessels.[147,148] Studies indicated that the levels of NO and neuronal nitric oxide synthase (nNOS) in rodent muscles were elevated due to increased muscle fiber contractility or hypoxia.[149,150] A study involving males who performed bilateral knee extension exercises for 8 weeks found that combining low-load resistance exercise with BFRE led to increased expression of HIF-1α, HIF-1β, and VEGF mRNA in skeletal muscle, surpassing the effects of conventional resistance training. In addition, the study observed elevated gene expression of inducible nitric oxide synthase (iNOS), which contributed to enhanced muscle growth.[151] Mice subjected to a 4-week treadmill running exhibited increased levels of nNOS in the tibialis anterior muscle, highlighting the exercise-induced upregulation of nNOS.[152] A study explored the potential of ketone ester supplementation to enhance pro-angiogenic factors and promote muscular angiogenesis in male volunteers undergoing rigorous endurance training for 3 weeks.[153] Participants received 25 g of ketone ester after each training session. The results showed that combining ketone ester supplementation with exercise increased capillary connections, capillary-to-fiber perimeter ratio, and elevated eNOS and VEGF expression levels. This was attributed to increased erythropoietin secretion and enhanced VEGF response to exercise. These findings suggest that modulating the NOS/NO system can improve muscle function by facilitating angiogenesis.
Research has also shown that certain microRNAs play a role in exercise-induced muscle neovascularization by being transported through extracellular vesicles (EVs). A study found that after 4 weeks of treadmill exercise, rats exhibited increased release of circulating EVs containing elevated levels of miR-125a-5p. These EVs enriched with miR-125a-5p facilitated perfusion recovery in muscle tissue by targeting the Akt/eNOS pathway and endothelin-converting enzyme 1 (ECE1), thereby promoting angiogenesis.[154] The activation of Notch1 and the phosphorylation of Akt/eNOS are essential for improving endothelial cell function.[155] Mice subjected to nine consecutive days of treadmill exercise exhibited increased circulating levels of liver-specific miR-122-5p, which was transported via EVs. The exercise-induced increase in hepatic-derived EVs containing miR-122-5p enhanced fatty acid utilization. Furthermore, miR-122-5p activated 1-acyl-sn-glycerol-3-phosphate acyltransferase in endothelial cells and increased VEGF levels in skeletal muscles, resulting in higher capillary density. These findings suggest that miR-122-5p has potential therapeutic effects in promoting angiogenesis by activating VEGF signaling.[156] Exercise not only enhances muscle size and performance but also promotes tissue healing. During physical activity, skeletal muscle releases various myokines, including FSTL1, IL-6, IGF-1, and irisin. These myokines play a crucial role in regulating glucose and lipid metabolism, while also stimulate the release of other myokines that support angiogenesis. Furthermore, they interact with key factors involved in angiogenesis, such as VEGF, NOS, and MMP, to facilitate the formation of new blood vessels, ultimately promoting angiogenesis.[157]
Exercise counteracts muscle aging
Aging is marked by a multifaceted interplay among declining muscle function and mass, impaired circulatory dynamics, and diminished physical performance, culminating in compromised locomotor function in older adults.[158] Aged skeletal muscle exhibits diminished responsiveness to anabolic stimuli, contributing to muscle mass and strength loss, and ultimately predisposing individuals to age-related frailty and functional decline. Studies have demonstrated that elderly individuals need increased blood flow to their muscles to promote muscle fiber hypertrophy and activate satellite cells.[159] Aging is associated with a decline in NO bioavailability and a decrease in VEGF expression, leading to a reduction in vascular density and subsequent impairment in blood flow.[160] The capacity of skeletal muscle to stimulate capillary growth is diminished in elderly women, coinciding with reduced proliferation of microvascular endothelial cells within the muscle tissue and decreased levels of VEGF.[161] Skeletal muscle exhibits a remarkable capacity to increase its metabolic rate during exercise, particularly when in an active state. In response to physical activity, the muscle undergoes adaptive changes, including the stimulation of mitochondrial biogenesis, modulation of fiber composition, and promotion of angiogenesis, which facilitates the growth of new blood vessels to meet the increased oxygen and nutrient demand.[162] A comprehensive multi-tissue single-cell RNA sequencing analysis demonstrated that aging resulted in alterations to the quantity or relative distribution of skeletal muscle, neural, and hematopoietic stem cells. In contrast, exercise partially mitigated these compositional shifts in older mice. Specifically, exercise facilitated the release of sapiens secreted phosphoprotein 1 from muscle fibers, which might enhance skeletal muscle homeostasis and regeneration in aged animals by modulating immune responses.[163]
Exercise promotes the remission of kidney-related diseases and exerts positive regulatory impacts on long-term inflammation, abnormal lipid levels, resistance to insulin, and age-related muscle loss.[164] The findings of a study indicated that older men (72 ± 1 years) experienced an augmentation in the size of type II muscle fibers, along with an increase in the quantity of capillary connections per muscle fiber and the exchange index between capillaries and muscle fibers of both type I and type II after participating in 12 weeks of resistance training.[165] The results showed an increase in gas transport and nutrient absorption, resulting in better skeletal muscle mass and function even as individuals age. Enhanced mitochondrial function and antioxidant defenses may also contribute to healthier aging muscles. Endurance exercise training can have numerous benefits for elderly individuals, including increased oxidative enzyme activities, enhanced capillarization, and even gains in skeletal muscle mass. These advantages are particularly pronounced when compared to elderly individuals who do not engage in regular endurance exercise training.[166] Resistance training and HIIT in elderly males (66.5 ± 3.8 years), consistent-load cycling in elderly individuals (69 ± 7 years), and cycling at 75% of the individual’s maximal oxygen uptake (VO2max) in elderly males and elderly females (67–75 years) experienced similar enhancements in aspects associated with the development of capillaries. The activity of succinate dehydrogenase and citrate synthase was found to be improved, respectively, indicating enhanced muscle oxidative capacity and mitochondrial respiratory capacity.[167,168,169] Women aged 61 ± 4 years, with or without regular exercise habits such as running or cycling over the past 20 years, executed a single-leg knee extensor exercise for a duration of 3 min. The vastus lateralis muscle in individuals with a high-intensity exercise routine showed significant increases in capillary–fiber ratio, capillary density, VEGF, and mitochondrial oxidative phosphorylation complexes I, II, and V levels. Stretching training is particularly well-suited for individuals who are unable to engage in vigorous exercise due to its low intensity, making it especially beneficial for older individuals with a lower risk of injury. The muscle stretching in rehabilitation patients helped prevent muscle atrophy in the lower limbs that are immobilized.[170] Male rats at the age of 20 months underwent four weeks of ankle fixation and stretch. The blood flow in the plantar flexor muscles was augmented during limb stretching, resulting in enhanced endothelium-dependent vasodilation in muscular arterioles, microvascular adaptations such as increased volume and capillary density per muscle fiber.[171] The stretched limb also showed increased levels of eNOS, HIF-1α, and VEGF. The adjustments helped improve the flow of blood to the muscles during exercise in older muscles that were subjected to daily passive stretching. Human double minute-2 (HDM2) has been recently linked to the promotion of angiogenesis and inflammation by activating VEGF-A.[172] Inactive young men and older adults (50 to 75 years old) took part in a six-week progressive cycling exercise program, with different frequencies showing upregulated expression of PECAM-1 and HDM2 proteins in skeletal muscle, regardless of age. This was associated with a rise in capillarization levels, indicating metabolic cross-talk that governs the metabolic adaptations of endothelial cells.[173]
Brain
Exercise-induced cerebral angiogenesis
During embryonic and postnatal brain development, angiogenesis is robustly active, with vascular sprouting mediated by endothelial tip cell filopodia intruding into central nervous system tissues to establish a functional vascular network.[174] The formation of vessels is suspended during the developmental process, whereas angiogenesis in the healthy adult brain is primarily maintained in response to particular stimuli like injury or cerebrovascular malformation.[175] Microvessels play a crucial role in maintaining and enhancing the neurovascular network, which subsequently improves brain function. In disease states, both vascular density and cerebral blood flow are diminished, leading to neurological dysfunction and cognitive impairment. This outcome is closely associated with brain microvascular injury.[176] Inducing angiogenesis in the ischemic brain promotes neuronal survival by enhancing the production of neurotrophic factors and chemokines. Increased vascularization around the infarcted area is associated with improved survival, suggesting that the angiogenic response following a stroke plays a critical role in nervous system recovery. Moreover, the maturation of newly formed capillaries results in significant improvements in sensory and motor function in stroke-affected mice.[177] A study has demonstrated that following cerebrovascular injury, meningeal lymphatic vessels exhibit an immediate and robust response by rapidly infiltrating the damaged brain parenchyma. These vessels facilitate the drainage of interstitial fluid and guide the growth trajectory of neovascularization. Through physical adhesion, these lymphatic vessels direct the extension of new blood vessels along their surfaces into the injured brain region, thereby contributing to the reconstruction of the cerebral vascular network.[178]Figure 1 illustrates the molecular mechanisms of exercise-induced angiogenesis or lymphangiogenesis in various organs.
Figure 1.
Molecular mechanisms of exercise-induced angiogenesis and lymphangiogenesis in various organs. Exercise promotes cerebral angiogenesis either through directly up-regulating VEGF, VEGFR-2, FGF-2, IGF-1 in the prefrontal cortex or hippocampus, activating the NOS/NO axis in the cerebral cortex, or by up-regulating HCAR1 and activating the PI3K/ ATK or ERK1/2 pathway, thereby regulating VEGF-A in the hippocampus. Exercise promotes angiogenesis in the heart by directly up-regulating HIF-1α, VEGF, miR-126, miR-210, or activating DDAH1 in the myocardium, thereby activating the Caveolin-1, R-Ras/AKt/GSK3β pathways. Cardiac lymphangiogenesis is induced by exercise through up-regulating VEGFC, VEGF-D and VEGF-3. The activation of VEGF-3 further upregulates LYVE-1, Podoplanin and Prox1. Furthermore, exercise-induced muscle angiogenesis is mainly accomplished by activating the HIF-1α/VEGF, β-AR/PGC-1α/ERRα, VEGF-A/VEGF-2, NOS/NO axes, upregulating IL-6, CXCL, irisin, FSTL1, IGF, or stimulating the generation of exosomes carrying specific miRNAs. Finally, exercise can also increase the levels of MMP-9, VEGF, CD34, VEGFR-2, HIF-1α, EPCs, and miR-221/222 in the circulatory system, thereby promoting angiogenesis. AGTAP1: 1-acyl-sn-glycerol-3-phosphate acyltransferase; Akt: Protein kinase B; β-AR: β-adrenergic receptor; CXCL: Chemokine (C-X-C motif) ligand; DDAH1: Dimethylaminohydrolase 1; ECE1: Endothelin converting enzyme 1; eNOS: Endothelial nitric oxide synthase; EPCs: Endothelial progenitor cells; ERK1/2: Extracellular signal regulated kinases 1/2; ERRα: Estrogen-related receptor α; FGF-2: Fibroblast growth factor 2; FSTL1: Follistatin-like protein 1; GSK3β: Glycogen synthase kinase 3β; HCAR1: Hydroxy-carboxylic acid receptor 1; HIF-1α: Hypoxia-inducible factor-1α; IGF-1: Insulin-like growth factor-1; IL-6: Interleukin 6; LYVE-1: Lymphatic vessel endothelial receptor-1; MMP-9: Matrix metalloproteinase-9; NO: Nitric oxide; NOS: Nitric oxide synthase; PGC-1α: Peroxisome proliferator activated receptor-γ coactivator-1α; PI3K: Phosphoinositol-3-kinase; prox1: Prospero homeobox protein 1; R-Ras: Related RAS viral (r-ras) oncogene homolog; VEGF: Vascular endothelial growth factor; VEGF-A: Vascular endothelial growth factor A; VEGF-C: Vascular endothelial growth factor C; VEGFR-2: Vascular endothelial growth factor receptor 2; VEGFR-3: Vascular endothelial growth factor 3; VEGF-D: Vascular endothelial growth factor D.
Exercise promotes brain injury repair by promoting the growth of endothelial cells in the brain, which control the transfer of essential substances and waste materials between the bloodstream and the brain. In addition, exercise also promotes angiogenesis and supplies the necessary substances to improve neuronal function and overall cognitive performance by inducing the development of blood vessels within the brain.[179] Research on the vascular niche in neurogenesis implies that enhanced brain function and structure are linked to increased vascularization. Analyzing post-exercise capillary changes may serve as a useful indicator for understanding the dynamic relationship between neuronal and vascular adaptations.[180] Rat exposed to daily wheel running under both normal and high CO2 conditions revealed that resting cerebral blood flow remained stable in normal circumstances but increased in response to elevated CO2 levels. Prolonged exercise induced significant capillary expansion in the brain, especially in the motor regions of the cerebral cortex, after only 30 days. Exercise stimulated increased expression of CD61 integrin during the development of capillaries in the motor region of the brain, indicating enhanced angiogenesis and neurovascular plasticity. This expansion of capillary reserve supported improved cognitive ability and increased physical coordination.[181] Another rat model engaged in daily exercise induced cerebral vasodilation, particularly an increase in the diameter of small blood vessels. This dilation response was primarily observed under hypoxic conditions, while changes in vessel diameter were not significant under normoxic conditions.[182] The genes for angiogenesis, including VEGF and VEGFR2, were impacted in the hippocampus after the exercise, while neuropilin 2 and mTOR expressions were regulated after 24 h.[183] The positive influences of exercise on hippocampal plasticity might be further augmented by enhanced angiogenesis and neurogenesis. Previous research has demonstrated that HIIT stimulates the release of lactic acid from skeletal muscles into the bloodstream. Interestingly, studies have also found that lactate injections can increase cerebral expression of VEGF-A, a key protein involved in angiogenesis.[184] HIIT and L-lactate injections stimulate the growth of vascular endothelial cells by activating the hydroxy-carboxylic acid receptor 1 (HCAR1). This activation leads to increased levels of VEGF-A protein and the formation of new blood vessels in the hippocampus of mice brains. Notably, mice lacking the HCAR1 gene did not exhibit this effect. Furthermore, the study revealed that the PI3K/Akt and extracellular signal-regulated kinases 1/2 (ERK1/2) signaling pathways played a crucial role in regulating VEGF-A expression, shedding light on the underlying mechanisms by which exercise influenced brain function.[185] Furthermore, rats with voluntary wheel running for two weeks showed elevated levels of FGF-2, IGF-1, and VEGF-A mRNA in the prefrontal cortex and hippocampus. In addition, the physical training was also associated with the reduced DNA methylation levels at specific CpG sites, suggesting that exercise might regulate VEGF expression by influencing DNA methylation patterns.[186] A study also explored the changes in the expression of NOS and angiogenic factors in the rat cerebral cortex that engaged in daily treadmill running. Significant differences were found in FGF-2 and endostatin expressions, and these effects were reduced after supplement with NG-nitro-l-arginine methyl ester, suggesting that NO was involved in part of the angiogenesis process.[187]
Exercise counteracts cerebral aging
Extensive research has shed light on the characteristics and phenotypic changes that occur in the brain during aging, revealing alterations in mitochondrial structure, protein expression levels, and genetic profiles.[188,189,190] The age-related deterioration of microvascular endothelial function and phenotype is a critical factor in the development and progression of brain diseases. As individuals age, there is a decrease in capillary density, along with impaired vasodilation of vascular endothelial cells and disrupted neurovascular coupling mediated by the endothelium. These changes lead to reduced cerebral blood flow and cognitive decline.[191,192] Furthermore, aging-induced modifications in the microvascular endothelium compromise the integrity of the blood–brain barrier, thereby promoting neuroinflammation and exacerbating cognitive decline.[193,194,195] It has been showed about 10% of cerebral microvascular endothelial cells undergo cellular senescence in the aged mouse brain.[196] A single-cell-based aging clocks study found that the proliferative neural stem cells in the subventricular zone decline with age, accompanied by the upregulation of inflammation (IFI27) and lipid metabolism genes (AC149090.1). However, exercise has been shown to have a rejuvenating effect on oligodendrocytes and neural stem cells, effectively reversing the age-related decline in genes responsible for proliferation and neurogenesis.[197] Furthermore, it was observed that the integrity of meningeal lymphatic vessels and the efficiency of cerebrospinal fluid drainage progressively deteriorate with age, consequently impacting the clearance of cerebrospinal fluid macromolecules.[198]
A recent spatiotemporal transcriptomic analysis has demonstrated a gradual decrease in the specificity of neuroblastocytes and vascular endothelial cells during the aging process. Following exercise intervention, endothelial cells, pericytes, vascular smooth muscle cells, and neuroblasts exhibited rejuvenated characteristics.[199] Female aged rats underwent a daily treadmill exercise showed increased numbers of small blood vessels within the cerebral vasculature. In addition, the act of exercising led to a notable increase in four isoforms of VEGF mRNA expression (120, 144,164,188) and protein in this group of aged rats.[200] Middle-aged female mice (11–13 months) exhibited reduced signs of aging in the hippocampal astrocytes and myelin, as well as an increase in VEGF after six weeks of running wheel exercise.[201] Repetitive treadmill running in middle-aged female rats (14 months old) showed a higher rate of capillary growth after exercise. This resulted in a notable rise in the overall cortex volume and the length and surface area of capillaries when compared to non-exercise group.[202] Chronic swimming exercise in aged rats (23–24 months) elicited potential therapeutic benefits, including attenuation of age-related declines in cerebral capillary vascularity and blood perfusion, as well as reduction in oxidative stress. Exercise-induced upregulation of eNOS and VEGF resulted in enhanced microvascular perfusion in the aged cohort. These findings suggest that exercise training may mitigate age-related microvascular dysfunction and cerebral hypoperfusion, thereby promoting healthy brain aging.[203] These findings showed that an aging population can still elicit an angiogenic response to chronic physical exercise and may contribute to maintaining youthful brain function. The exercise-induced structural changes are linked to improved function of peripheral endothelial cells and the enlargement and increased reactivity of astrocytes, along with counteraction of dysregulation of myelin and vascular function. Furthermore, it indicated that the increase in blood vessel formation in the cortex could potentially enhance spatial learning abilities. This provides important implications for future studies on slowing down or avoiding cognitive impairment caused by aging. The process of exercise-induced angiogenesis and its role in anti-aging has been shown in Figure 2.
Figure 2.
Schematic diagram of exercise-induced angiogenesis in the resistance to aging. Exercise promotes the development of new blood vessels by up-regulating eNOS and VEGF in the aging brain, eNOS, HSP70, HIF-1α and VEGF in the aging heart, VEGF, CXCR4, JAK-2 and EPCs in the aging blood vessel, and VEGF, eNOS, HIF-1α, HDM2, PECAM-1 and VEGF-A in the aging muscle, thereby alleviating the decline in organ function related to aging. CXCR4: CXC chemokine receptor 4; eNOS: Endothelial nitric oxide synthase; EPCs: Endothelial progenitor cells; HDM2: Human double minute 2; HIF-1α: Hypoxia-inducible factor-1α; HSP70: Heat shock protein 70; JAK-2: Janus kinase-2; PECAM-1: Platelet endothelial cell adhesion molecule; VEGF: Vascular endothelial growth factor; VEGF-A: Vascular endothelial growth factor A.
Exercise protects against cerebrovascular diseases
Angiogenesis enhances the circulation of blood in the vicinity of an ischemic stroke, leading to a reduction or elimination of necrotic tissue and inflammatory substances.[204] Research conducted on rats has demonstrated that angiogenesis is crucial for increasing blood circulation and facilitating the recovery process in the brain after an ischemic injury.[205] Regular exercise has been shown to prevent these declines, supporting the survival of nerve cells and blood vessel cells, and improving hippocampal vascular structure. It improves both the neurogenesis in the brain and cognitive function, whereas mice under chronic stress show fewer blood vessels in the dentate gyrus region of the hippocampus.[206] Running exercise was found to improve motor function, reduce neurological deficits, thereby mitigating brain damage. VEGFR-2, doppel, and platelet-derived growth factor receptor β (PDGFRβ) were significantly upregulated in the infarct center, as well as the adjacent cerebral cortex of mice.[207] Furthermore, the exercise has been demonstrated to enhance the functionality of exosomes derived from circulating CD34+/KDR+ EPCs. The miR-126 level exhibited a significant increase in the ipsilateral tissue following 2 days of ischemic stroke. Levels of brain-derived neurotrophic factor (BDNF), p-tropomyosin receptor kinase B (TrkB)/TrkB, and p-Akt/Akt were elevated within the brains of mice that had been engaged in exercise, potentially contributing to neurological recovery and neurogenesis.[208] Mice subjected to chronic restraint stress exhibited mitigated cognitive decline and vascular benefits when engaging in regular exercise. Notably, both intermittent high-intensity and moderate-endurance treadmill running exerted neuroprotective effects, preventing stress-induced cognitive impairment. Specifically, these exercise regimens enhanced the survival of CD31-positive endothelial cells and increased cerebral blood vessel density.[209] Exercise preconditioning, adaptive exercise, and rehabilitation exercise have been shown to promote angiogenesis in the brain, leading to increased microvascular density. Notably, a higher density of microvasculature is associated with a markedly improved prognosis in the region impacted by diminished blood circulation for patients who have suffered from stroke.[210] Preconditioning exercise before ischemia may protect against future severe injury by stimulating the growth of new blood vessels, regulating inflammatory reactions, and inhibiting cell apoptosis.[211] Preconditioning exercise, specifically aerobic exercise, facilitated cerebral microvascular development and overall brain health of rats. This exercise regimen enhances the activation of astrocytes and promotes angiogenesis in peri-ischemic regions, thereby mitigating the impact of brain ischemia.[212] Furthermore, the repetitive exercise not only significantly decreased the amount of damaged tissue and neurological issues but also boosted the production of neurotrophic factors, such as midkine (MK) and BDNF. In rats with middle cerebral artery occlusion (MCAO), treadmill training for 14 days led to enhanced recovery after stroke by increasing microvessel density and cerebral blood flow in ischemic areas. Exercise was found to significantly increase the density of microvessels and the number of CD31+ cells in rats, indicating that early locomotor exercise promotes angiogenesis. These newly formed vessels contribute to enhanced cerebral blood flow in brain areas affected by ischemia.[213,214] A study found that MCAO rats that underwent 2 weeks of running exercise, preceded by a 3-day adaptation period, showed increased density of new blood vessels in the affected striatum and significantly reduced infarct size. The findings suggested that rota-rod training improved balance and coordination in rats with MCAO, and faster treadmill training also had beneficial effects on the functional recovery of rats by stimulating increased angiogenesis.[215] The regeneration of peripheral vessels was facilitated by metalloproteinase membrane type 1-metalloprotease (MT1-MMP). Rats that underwent a three-day adaptive running program for two weeks showed reduced infarction area and improved modified neurological function scores compared to the MCAO group. The findings showed a notable increase in new blood vessel formation around areas of reduced blood flow in the brain. This was linked to higher levels of MT1-MMP expression in endothelial cells near injured areas of the brain.[216] A separate study revealed that 4 weeks of recovery exercise following MCAO stimulated the release of basic fibroblast growth factor (bFGF), a key mediator of angiogenesis and tissue repair. In addition, the treadmill exercise resulted in higher expressions of VEGF and VEGFR-2/CD34. Immunohistochemical analysis using BrdU/Nestin staining revealed an increase in neural progenitor cells, indicating enhanced neurogenesis, angiogenesis, and ultimately, reduced neuronal damage.[217] Cerebral infarction, also known as brain infarction, is characterized by the death of brain or retinal cells due to prolonged inadequate blood supply, leading to oxygen deprivation and cellular death. This results in various physical and cognitive impairments, significantly impacting patients’ quality of life.[218] Insufficient blood flow to the cerebrovascular system can lead to cerebral infarction, resulting in insufficient oxygen and energy supply to the brain tissue. This deficiency of essential nutrients exacerbates brain tissue dysfunction, leading to hypoxia and necrosis of nerve cells. Research suggests that promoting angiogenesis can enhance recovery from stroke-related physical and mental impairments, leading to improved outcomes for survivors.[219] Studies have shown that both control and exercise groups exhibit neovascularization around the infarcted area, with peak angiogenic activity occurring on day 7 post-ischemia.[220] The number of CD31-positive cells showed a notable rise on the seventh and fourteenth days after ischemia in the exercised group, indicating that exercise effectively promoted post-infarct angiogenesis. In addition, it was observed that from the seventh day onwards, the severity scores for neurological function improved more rapidly in the exercise group, suggesting that exercise had a positive impact on promoting recovery of neurological function and angiogenesis following cerebral infarction in rats.
Others
Exercise protects against other diseases
Exercise-induced angiogenesis and lymphangiogenesis may also offer protective effects against metabolic diseases, such as diabetes. Diabetes not only disrupts blood sugar regulation but also has long-term consequences for the vascular system, making exercise a potentially valuable strategy for mitigating these effects.[221] Recently, Abdelsaid et al[222] demonstrated that exercise influenced EV-mediated vascular adaptation in diabetic mice. Following a two-week running program, diabetic mice exhibited improved blood vessel growth. Exercise stimulated the production of EVs, which delivered increased levels of ATPase, copper transporting, alpha polypeptide (ATP7A), and superoxide dismutase3 (SOD3) to endothelial cells, enhancing markers of endothelial function and angiogenesis, including VEGF. Notably, these benefits occurred without significant weight changes. These results indicated that regular exercise was a beneficial strategy for addressing various health issues, including diabetes, muscle loss, high blood pressure, and obesity. Research has shown that impaired angiogenesis in individuals with diabetes can compromise tissue protection, highlighting the importance of promoting angiogenesis as a potential therapeutic strategy for managing diabetic complications.[223] A study involving db/db mice found that regular exercise, in the form of running on a wheel for 2–6 weeks, improved endothelial function. While 2 weeks of exercise did not impact C-reactive protein (CRP) levels, extending the exercise period to 6 weeks led to decreased CRP levels and sustained restoration of endothelium-dependent vasodilation, ultimately enhancing endothelial cell function in diabetic mice.[224] In another study, streptozotocin-induced diabetic rats that underwent daily ladder climbing training for 4 weeks showed increased plasma NO concentrations, which may contribute to improved vascular function and insulin sensitivity. In addition, research by Karimian et al[225] found that exercise-induced increases in plasma nitrite levels were associated with enhanced capillary density in the soleus muscle, highlighting the positive effects of exercise on vascular function and angiogenesis in diabetic models.[225] The exercise-induced elevation in miR-126 levels in the mice resulted in enhanced cardiac angiogenesis through upregulation of VEGF expression, which is beneficial for managing diabetic cardiomyopathy. PI3K and Raf1 pathways were also involved in this progress.[226] These discoveries have elucidated the critical role of angiogenic mechanisms in aerobic exercise among individuals with diabetes, particularly highlighting miR-126 and its potential as a valuable therapeutic target for pathological conditions in cardiac tissues. In addition, a study has shown that the expression of eNOS was increased in the myocardium of male diabetic db/db mice after eight weeks of running. This exercise also led to an elevation in VEGF-A and HIF-1α mRNA levels, as well as a reduction in IL-6, tumor necrosis factor α (TNF-α) protein expression, and IL-1β expression, thereby contributing to the improvement of diabetic cardiac function and blood vessel formation.[227] The levels of important cytokines associated with the onset of endothelial dysfunction and insulin resistance in cardiac muscle declined after exercise. In addition, there was an enhancement in vascular function due to angiogenesis, leading to capillarization and improved blood flow. Exercise promotes angiogenesis and reduces cytokine expression, leading to improved glucose metabolism as enhanced blood flow facilitates insulin transport, promoting glucose disposal and improving insulin sensitivity. Diabetic neuropathy (DN) frequently occurs as a complication of diabetes, and its development is impacted by a range of factors. One significant factor in the advancement of DN is the reduction in angiogenesis, which may be associated with elevated levels of glucose in the bloodstream and other metabolic abnormalities related to diabetes. In addition, inflammation and oxidative stress also contribute to inhibiting angiogenesis in individuals with diabetes.[228] A four-week treadmill running protocol in diabetic rats demonstrated that either IGF-1 or exercise alone increased the number of blood vessels in the sciatic nerve by increasing VEGF-A. Interestingly, research showed that combining IGF-1 supplementation with exercise significantly increased the number of CD31-positive vascular endothelial cells and improved sciatic nerve structure in diabetic rats, compared to untreated diabetic rats.[229] The results indicated that IGF-1 and physical activity might have potential as a treatment for DN.
Obesity has been found to disrupt the lymphatic system in several ways, including reducing the number of lymphatic vessels, decreasing lymph fluid pumping, impairing immune cell movement, increasing lymphatic vessel permeability, and altering gene expression in lymphatic endothelial cells.[230] Obese mice engaging in treadmill running over a period of 6 weeks exhibited significant lymphatic function improvement, regardless of any reduction in body weight. Exercise alone decreased accumulation of cells involved in inflammation in peripheral lymphatic vessels. The reduction in iNOS levels suggested a potential anti-inflammatory effect. Furthermore, exercise restored normal levels of genes specific to the lymphatic system, such as VEGFR-3 and prospero homeobox protein 1 (Prox1).[231] These results highlighted the possibility of therapeutic benefits from exercise in alleviating obesity-related lymphatic dysfunction. Figure 3 illustrates the molecular mechanisms by which exercise induces angiogenesis against different diseases.
Figure 3.
Exercise-induced angiogenesis and lymphangiogenesis can be used as a potential therapeutic for cardiovascular, brain, and metabolic diseases. Exercise boosts the number of blood vessels by activating Notch-1/Akt/eNOS and EPCs to alleviate hypertension, and upregulates SIRT1 and VEGF to decrease thrombosis formation. Cardiac angiogenesis induced by exercise improves I/RI and heart failure by up-regulating FGF-2, VEGF, and HIF-1α. Exercise can also activate the VEGF/PI3K/eNOS, FSTL1/TGF-β/Smad2/3, and B1R/B2R/VEGF/eNOS axes to induce angiogenesis and protect against MI. The pro-angiogenic factors upregulated by exercise, such as VEGFR-2, bFGF, PDGFRβ, VEGF, MT1-MMP, and EPCs, also play a role in ameliorating cerebral stroke and cognitive impairment. In addition, it has been found that the upregulation of SOD3, VEGF, NO, eNOS, VEGF-A, HIF-1α, IGF-1, and miR-126 stimulates angiogenesis, and the upregulation of VEGFR-3 and Prox1 increases lymphangiogenesis. These have also been identified as important factors for exercise to improve metabolic diseases such as diabetes, its complications, and obesity. Akt: Protein kinase B; bFGF: Basic fibroblast growth factor; B1R and B2R: Bradykinin 1 and 2 receptor; eNOS: Eendothelial nitric oxide synthase; EPCs: Endothelial progenitor cells; FGF-2: Fibroblast growth factor 2; FSTL1: Follistatin-like protein 1; HIF-1α: Hypoxia-inducible factor-1α; I/RI: Myocardial ischemia-reperfusion injury; IGF-1: Insulin-like growth factor-1; MI: Myocardial infarction; miR-126: MicroRNA-126; MT1-MMP: Metalloproteinase membrane type 1-metalloprotease; NO: Nitric oxide; PDGFRβ: Platelet-derived growth factor receptor beta; PI3K: Phosphoinositol-3-kinase; Prox1: Prospero homeobox protein 1; SIRT1: Sirtuin 1; SOD3: Superoxide dismutase 3; TGF-β: Transforming growth factor-β; VEGF: Vascular endothelial growth factor; VEGF-A: Vascular endothelial growth factor A; VEGFR: Vascular endothelial growth factor receptor.
In summary, exercise has a profound impact on various physiological systems, rejuvenating tissues and organs, and enhancing overall health and well-being. Adopting and maintaining regular exercise habits is essential for preserving physiological function and mitigating age-related decline. Details of the different types of exercise-induced angiogenesis and lymphangiogenesis are summarized in Table 1.
Table 1.
Different types of exercise promote angiogenesis and lymphangiogenesis in physiological and pathological conditions.
| Type | Protocol | Subject | Tissue | Results | Indicators | Clinical trials | References |
|---|---|---|---|---|---|---|---|
| Cycling | Consisted of six to seven sets of 20-sec cycling session, 4 days/week for 6 weeks | Males | Skeletal muscle | Increased muscle adaptation and promoted angiogenesis |
COL4A1↑ COL4A2↑ FGF-6↑ KDR↑ NRP1↑ |
No | [19] |
| Treadmill running | Moderate intensity: 18 m/min with 5° incline; high intensity: 18 m/min with 30° incline. Both intensities were performed 1 h/day, 5 days/week for 13 weeks | Male rats | Heart | Induced physiological cardiac hypertrophy, improved cardiac function, and increased capillary density | Capillary density↑ | Lack of human trials | [20] |
| Treadmill running | Gradually increased to 36 min/session, 40 m/min with 15% incline, 5 times/week for 10 weeks | Male rats with high-fat diet | Adipose | Increased capillary density and anti-inflammatory macrophage | Capillary density↑ | Lack of human trials | [21] |
| Wheel running | Voluntary running for 5 weeks | Male rats | Brain | Increased capillary diameter and expanded endothelial cell nuclei diameter | Sprouting angiogenesis↑ | Lack of human trials | [22] |
| Treadmill running | Gradually increased to 12 m/min, 30 min/day, 5 days/week for 4 weeks | Female rats with lymphedema | Hind limb | Increased lymphatic vessels density and improved lymphatic system | Lymphatic vessel density↑ | Lack of human trials | [23] |
| Cycling | Four cycling tests in normoxic and hypoxic conditions until exhaustion | Males | Blood | Facilitated the bioavailability of angiogenic and extracellular matrix-related biomarkers | VEGF↑ MMP-9↑ MMP-2↓ |
No | [43] |
| Blood-flow-restricted exercise | 21 min of exercise consisting 9 min warm-up, 6 × 30-sec sprint, and 6 × 90-sec cool-down with arm and leg cuffs | Males and females | Blood | Promoted angiogenesis and improved endothelial function | PECAM-1↑ VEGFR-2↑ CD34↑ |
No | [44] |
| Flat bench press, dumbbell curl, dumbbell squat, and standing dumbbell row | Performing 3 sets of 12 repetitions for each of the 4 exercises, at intensities of 60%, 70%, and 80% of the maximum repetitions in a single session | Premenopausal females | Blood | Increased EPCs and angiogenic factors | EPCs↑ SDF-1α↑ VEGF↑ HIF-1α↑ EPO↑ |
No | [52] |
| Sprint | Sprint interval: 4 × 30-sec maximal effort sprints with a 4.5-min rest; sprint continuous training: sustained maximal effort sprint with no rest, 3 days/week for 12 weeks | Females | Blood | Increased cardio-respiratory fitness and stem cell mobilization | CD34+ cells↑ | Yes | [53] |
| Running, sprint, and plyometric | Aerobic training: running in 3 season phases for 12 weeks; Anaerobic training: sprint and plyometric 3 to 4 times/week for 12 weeks | Male athletes | Blood | Increased maximal oxygen uptake and adaptation | CD34+ cells↑ RBCs↑ WBCs↑ Hemoglobin↑ Hematocrit↑ |
No | [54] |
| Cycling | Stationary cycling at 70% of O2max until total energy expenditure reached 598 kcal | Males and females | Blood | Increased CD62E+ endothelial microparticles in men and CD34+ microparticles in women | CD62E+ cells↑ CD34+ cells↑ |
No | [55] |
| Fitness and basketball | 3-Month basketball season, consisting of acute strenuous exercise testing and long-term basketball competition | Male basketball players | Blood | Improved cardiovascular fitness and exercise capacity | MiR-208b↓ MiR-221↑ |
No | [56] |
| Treadmill running | 30 min/day, 3 days/week for 12 weeks | Young males (26.3 ± 3.15 years) and elderly males (67.8 ± 3.38 years) | EPCs | Attenuated age-associated reduction in reparative capacity of EPCs | EPC activity↑ CXCR4↑ JAK-2↑ |
No | [71] |
| Cycling | 5 days/week for a total of 12 weeks | Patients with hypertension | EPCs | Lowered systolic and diastolic blood pressures and induced angiogenesis | EPCs↑ NOTCH-1↑ p-AKT↓ p-eNOS↓ |
Yes | [74] |
| Cycling | 3-4 times/week, 1 h for 8 weeks | Untrained female patients with hypertension | Skeletal muscle | Improved diffusion conditions and altered capillary structure and number | VEGF↑ TIMP-1↓ Capillary-to-fiber ratio↑ |
No | [75] |
| Ladder climbing | Consisted of a 1-cm grid inclined at 85° and performed 2 sets of 3 times/day for 2 min, 6 days/week for 4 weeks | Male mice with deep venous thrombosis | Inferior vena cava | Reduced weight and size of thrombus and collagen content, increased venous recanalization rates, and reduced inflammation |
Vegf ↑ Sirt1↑ |
Lack of human trials | [79] |
| Treadmill running | Aerobic exercise: 20 m/min for 30 min; anaerobic exercise: 35 m/min for 20 min for 1, 3, 7, and 10 days | Male rats | Heart | Increased concentrations of HIF-1α and VEGF in myocardium | Vegf↑ Hif-1α↑ |
Lack of human trials | [85] |
| Treadmill running | Gradually increased to 24 rotations/min, 60 min/day, 5 days/week for 30 or 45 days | Male mice | Heart | Promoted cardiac angiogenesis | Mmp-2↓ Mmp-9↑ CD31+ cells↑ |
Lack of human trials | [86] |
| Swimming | Gradually increased to 90 min/day, 5 days/week for 8 weeks | Male DDAH1 KO mice and DDAH1flox/flox mice | Heart | Promoted cardiac angiogenesis | Vegf↑ Caveolin-1↑ Ddah1↑ |
Lack of human trials | [88] |
| Swimming | Moderate intensity: 60 min/day, 5 days/week for 10 weeks with 5% additional weight loading; high intensity: had the same protocol as moderate exercise for the first 8 weeks, then exercised twice a day starting in week 9, 3 times/day in week 10 | Female rats | Heart and skeletal muscle | Promoted cardiac angiogenesis | MiR-126↑ Vegf↑ eNos↑ Capillary-to-fiber ratio↑ |
Lack of human trials | [89] |
| Wheel running | Running for 6 weeks with or without garlic supplement | Male rats | Heart | Garlic combined with exercise enhanced cardiac angiogenesis and improved serum lipid profile | MiR-126↑ MiR-210↑ CD31+ cells↑ |
Lack of human trials | [90] |
| Swimming | Gradually increased to 180 min/day, twice a day for 3 weeks | Male and female mice | Heart | Increased cardiac lymphatic vessel density and induced physiological cardiac growth | Lyve-1↑ Vegf-c↑ Vegf-d↑ Vegfr-3↑ Igf-1↑ Reln↑ Pdpn↑ |
Lack of human trials | [92] |
| Treadmill running | Level running: 20 m/min running per day for 30 min for 6 weeks with 0 degree decline; downhill running: Same protocol except at –20 degree decline | Female rats | Skeletal muscle and heart | Decreased lymphatic vessel density in skeletal muscle and increased lymphatic vessel density in cardiac tissue | Lyve-1↑ Pdpn↑ Vegf-c↑ Vegf-d↑ |
Lack of human trials | [94] |
| Treadmill running | Gradually increased to 60 min/day with 5% grade for 6 weeks | Elderly male rats with low-flow ischemia (24 months old) | Heart | Improved myocardial contractile function and recovery of the aged heart after ischemia-reperfusion | Hsp70↑ eNos↑ |
No | [105] |
| Wheel running | Voluntary wheel running was performed for eight consecutive weeks. | Male mice (young 2-month-old and aged 20-month-old or 22-month-old) | Heart | Remodeled lymphatic vasculature, improved lymphatic flow, and cardiac lymphatic function | Lyve-1↑ Pdpn↑ Vegfr-3↑ |
Lack of human trials | [107] |
| Treadmill running | Gradually increased to 16 m/min for 50 min, 5 days/week for 8 weeks | Male rats with post-MI | Heart | Increased cardiac angiogenesis in post-MI rat | Capillary density↑ | Lack of human trials | [109] |
| Treadmill running | Five sessions of interval running per week for 8 consecutive weeks, consisting of 30 min running at speeds of 29–36 m/min | Male rats with I/RI | Heart | Improved cardiac function and reduced infarct size |
Vegf↑ Fgf-2↑ Tsp-1↓ |
Lack of human trials | [110] |
| Treadmill running | Gradually increased to 50 min/day with 5° incline, 5 days/week for 10 weeks | Male rats with MI | Heart and blood | Exercise combined with L-arginine increased cardiac microvessel density and improved cardiac function |
Vegf↑ NO ↑ Capillary density↑ Capillary-to-fiber ratio↑ Angiostatin↓ |
Lack of human trials | [111] |
| Treadmill running and mechanical vibration | Running: between 7 min at 25 m/min and 3 min at 15 m/min for 1 h/day, 5 days/week for 4 weeks; mechanical vibration: at a frequency of 25 Hz with amplitude of 2 mm for twice a day, 38 min/day, 5 days/weeks for 4 weeks | Male rats with MI | Heart and skeletal muscle | Improved cardiac function, reduced fibrosis, and promoted angiogenesis | Fstl1↑ Tgf-β↑ Smad2/3↑ |
Lack of human trials | [113] |
| Treadmill running | Gradually increased to 1 h at a speed of 15 m/min per day, 5 days/week for 8 weeks | Male mice with MI | EPCs | Improved EPCs function, reduced cardiac dilatation, and infarct size | Akt↑ Gsk3β↑ |
Lack of human trials | [114] |
| Treadmill running | Gradually increased to 22 m/min for 30 min, one time/day for 4 weeks | Male rats with MI | Heart | Activated kallikrein-kinin system, especially B1 and B2 receptors, promoted cardiac angiogenesis |
Vegf↑ eNos↑ |
Lack of human trials | [116] |
| Treadmill running | Gradually increased to 50 min at a speed of 18 m/min with a 15° slope for 1 session per day, 5 days/week for 4 weeks | Male rats with HF | Heart | Combined food restriction with exercise improved strengthen balance of antioxidative defense system, as well as gene expression of angiogenic factors and decreased myocardial fibrosis |
Hif-1α↑ Vegf-a↑ eNos↑ |
Lack of human trials | [120] |
| Leg extension and leg curl, cycling, and stretching | HIIT: exercised for 3 min at 50% VO2peak + 4 × (4 min at 80% VO2peak + 3 min at 50% VO2peak), 3 sessions/week for 3 months; COM: exercised for 3 min at 50% VO2peak + 2 × (4 min at 80% VO2peak + 3 min at 50% VO2peak ) followed by 14 min of strength training, 3 sessions/week for 3 months | Male patients with chronic HF | Skeletal muscle | Enhanced angiogenesis-related gene expression |
VEGF↑ VEGFR-2↑ HIF-1α↑ ANG-1↑ ANG-2↑ TIE2↑ MMP-9↑ |
Yes | [121] |
| One-leg knee extension | Consisted of 60 repetitions/min of stretching with an intensity of 50% of baseline peak work rate, 3 times/week for 8 weeks | Male and female patients with chronic HF | Skeletal muscle | Increased levels of VEGF mRNA, improved muscle citrate synthase activity, as well as peripheral exercise capacity | VEGF↑ | No | [122] |
| HIIT combined with strength | HIIT: 4 cycles, consisted of 4 min at 80% VO2peak intensity and 3 min of recovery at 50% VO2peak intensity for 31 minutes; COM: 2 cycles, consisted of 4 min at 80% VO2peak intensity and 3 minutes of recovery at 50% VO2peak intensity for 17 minutes, followed by 14 min of strength training, 2–4 sets of 10–12 repetitions of each movement | Male patients with chronic HF | Skeletal muscle | Reversed skeletal myopathy and induced muscle hypertrophy |
IGF-1↑ Capillary-to-fiber ratio↑ |
Yes | [123] |
| Knee-extensor exercise | Gradually increased to 50 min/session/leg, 3 times/week for 8 weeks | Male patients with HFrEF and healthy subjects | Skeletal muscle | Increased muscle capillary density, muscle fiber cross-sectional area, percentage of type I fibers, and mitochondrial bulk density | VEGF↑ | No | [125] |
| Cycling | With more than 4 h of moderate and high-intensity exercise per week over the past 20 years | Postmenopausal females (61± 4 years) | Skeletal muscle | Increased femoral artery blood flow and oxygen uptake with higher muscle fiber capillarization and mitochondrial capacity | Capillary-to-fiber ratio ↑ Capillary density↑ VEGF ↑ |
No | [133] |
| Cycling | Aerobic training: 3 times/week for 30 min for 12 weeks; resistance training: 3 times/week and consisted of 3 sets of 4 exercises at 6–12 repetitions maximum for 9 weeks | Elderly males (65–74 years) | Skeletal muscle | Increased maximum oxygen uptake and capillary supply | Capillary-to-fiber ratio↑ | Yes | [134] |
| Treadmill running | Gradually increased to 30 m/min, 45 min/day, 5 days/week for 8 weeks | Male rats | Skeletal muscle and heart | Improved muscle metabolic efficiency and promoted angiogenesis |
Pgc-1α↑ Hif-1α↑ Vegf↑ FoxO3a↓ Murf-1↓ Atrogin-1↓ Capillary-to-fiber ratio ↑ |
Lack of human trials | [138] |
| Wheel running | Voluntary running for 14 days | Wild-type mice PGC-1-/- mice ERR-/- mice | Skeletal muscle | Increased capillary density | β-adrenergic↑ Errα↑ Pgc-1α↑ Vegf↑ |
Lack of human trials | [140] |
| Cycling, leg press and extension, chest press and horizontal row or vertical pull-down and shoulder press | Three times/week for 2 and 12 weeks | Males | Skeletal muscle | Increased cross-sectional area of type I and type II muscle fibers and capillary density |
VEGFR-2↑ HIF-1α↑ eNOS↑ Capillary-to-fiber ratio ↑ |
Yes | [141] |
| One-legged knee-extension | 45 min, 60 rpm for 10 days included 7 sessions | Males | Skeletal muscle | Induced pretranslational regulation of changes in VEGF | VEGF↑ | No | [143] |
| Treadmill running | Premassaged: 5 times/week for 3 weeks before training; massage: 5 times/weeks for the whole training; exercise:5 days/week for 10 weeks with speed gradually increasing to 0.5 m/s for 30 min | Rats | Skeletal muscle | Massage and physical exercise had synergistic impact on angiogenic markers |
Vegf-a↑ Fgf-2↑ |
Lack of human trials | [144] |
| Treadmill running | 30 min/day, 5 times/week for 8 weeks | Male rats with obesity | Skeletal muscle | Upregulated the mRNA expression of both myokines and angiogenesis factors |
mTOR↑ Vegf↑ Flt-1↑ |
Lack of human trials | [146] |
| Treadmill running | Gradually increased to 60 m/min on a 5% grade, 5 days/week for 10 weeks | Male rats | Skeletal muscle | Increased total NOS activity | Hsp90↑ Nos↑ |
Lack of human trials | [149] |
| Treadmill running | Gradually increased to 15 min at 1.9 km/h with 25% incline, or until reaching exhaustion | Female rats | Skeletal muscle | Increased NOS activity | Nos↑ | Lack of human trials | [150] |
| Bilateral knee extension | Low-load exercise with blood flow restriction: 80% of the arterial occlusion pressure; low-load: 3 sets of 14 repetitions at 20% 1RM; high-load: 3–4 sets of 8–10 repetitions at 80% 1RM, twice a week for 9 weeks | Males | Skeletal muscle | Increased expression of genes associated with hypoxia and angiogenesis |
HIF-1α↑ HIF-1β↑ VEGF↑ nNOS↑ iNOS↑ |
No | [151] |
| Treadmill running | Gradually increased to 4 m/min every 2 min with 15° incline, 45 min and 6 times/week for 28 days | Wild-type male micenNOS-KO male mice | Skeletal muscle | Increased nNOS expression | nNos↑ | Lack of human trials | [152] |
| Cycling | Consisted of 2 training sessions per day (6 days/week) and the load was gradually increased over the 3-week period (week 1: ~4600 kJ, week 2: ~6400 kJ, and week 3: ~9600 kJ) | Males | Skeletal muscle and blood | Exogenous ketosis was beneficial to exercise-induced muscular adaptation and angiogenesis | VEGF↑ EPO↑ eNOS↑ |
No | [153] |
| Treadmill running | Gradually increased to 30 m/min for 60 min, 5 days/week for 4 weeks | Male rats with unilateral femoral artery ligation | Skeletal muscle | Exercise-induced exosomal miR-125a-5p promoted angiogenesis | MiR-125a-5p↑ Ece1↓ p-Akt↑ p-eNos↑ |
Lack of human trials | [154] |
| Treadmill running | Gradually increased to 15 m/min for 40 min with 0° incline on 3 different days, and then trained at 18 m/min for 1 h for 9 continuous days | Male mice | Skeletal muscle and endothelial cell | Promoted angiogenesis through upregulation of liver-derived extracellular vesicle miR-122-5p and enhanced fatty acid utilization | MiR-122-5p↑ Agpat1↓ CD31↑ Vegf↑ p-Vegfr-2↑ |
Lack of human trials | [156] |
| Cycling, leg press and leg extension, chest press and horizontal row, vertical lat pull-down and abdominal crunches, biceps curl and triceps extension | Gradually increased to 80% of 1RM (8–10 repetitions) in the first 4 weeks; 4 sets of 8 repetitions were performed at 75–80% of 1RM in the 5th week, and 2 sets were increased to 3 sets starting in week 5, 3 times/week for 24 weeks | Elderly males (71 ± 1 years) | Skeletal muscle | Type II muscle fiber capillarization at baseline played an important role in inducing muscle fiber hypertrophy | Capillary-to-fiber ratio (unchanged) | No | [159] |
| Wheel running | Running for 3 weeks | Male mice (4- and 22-month-old) | Blood and muscle | Improved skeletal muscle homeostasis and regeneration by immune modulation | Igf-1↑ Spp1↑ Fgf-2 ↓ |
Lack of human trials | [163] |
| Cycling, leg press and leg extension | Gradually increased to 75–80% of 1RM (8–10 repetitions) in week 4 and after for 3 times for 12 weeks | Young males (26 ± 2 years) and elderly males (72 ± 1 years) | Skeletal muscle | Enhance skeletal muscle fiber capillarization | Capillary contacts ↑ Capillary-to-fiber perimeter exchange↑ |
No | [165] |
| Cycling, leg extension, leg press, and squat | High-intensity interval training: gradually increased peak power to 85% peak power; resistance training: consisting of the 3 exercises | Elderly men (66.5 ± 3.8 years) | Skeletal muscle | Increased myofiber capillarization and oxidative enzyme activity | Capillary-to-fiber ratio ↑ Capillary contacts ↑ |
Yes | [167] |
| Cycling | Consisted of 3 exercise sessions per week for 45 min, 3 times/week for 12 weeks | Males (22 ± 1 years) and elderly males (69 ± 7 years) | Skeletal muscle | Induced capillary angiogenesis and improved mitochondrial respiratory capacity | Capillarization↑ | No | [168] |
| Cycling | Consisted of 3 min of exercise at 0 W and increased to 20 W every minute and continuous exercise at 75% VO2max to exhaustion | Elderly males and elderly females (67–75 years) | Skeletal muscle | Increased oxidase activity and capillarization | VEGF↑ PGC-1α↑ p-AMPK↑ Capillaries per fiber ratio↑ |
No | [169] |
| Daily muscle stretching | Stretched for 30 min/day, 5 days a week for 4 weeks | Aged male rats (24 months) | Skeletal muscle | Increased blood flow, enhanced muscle vasodilatation and induced angiogenesis | Vegf↑ Hif-1α↑ eNos↑ Microvascular volume↑ Capillaries per fiber ratio↑ |
Lack of human trials | [171] |
| Cycling | The younger underwent a 6-week cycling consisting of 24 sessions of45 min, 4 times/week; the older underwent a 6-week cycling same as younger except for 3 times/week combined with 30 min of strength training | Young males (23.4 ± 0.7 years), elderly males and females (61.8 ± 1.7 years) | Skeletal muscle | Improved fitness level and muscle endothelial content | Hdm2↑ Pecam-1 ↑ |
No | [173] |
| Wheel running | Daily voluntary running for 30 days | Male rats | Brain | Increased forelimb motor activity, induced cortical angiogenesis, and not alter movement representation | Blood vessels density↑ | Lack of human trials | [179] |
| Wheel running | Daily voluntary running for 26 weeks | Male rats | Brain | Increased capillary and arteriole surface area densities, enhanced arteriole reactivity, as well as vasodilation | Blood vessels density↑ | Lack of human trials | [182] |
| Treadmill running | Gradually increased to 24 m/min for 100 min, 4 days/week for the first 4 weeks, and 2 days for the next 4 weeks | Male rats | Brain | The effect of exercise on the vascular endothelial growth factor system was acute rather than chronic |
Vegf↑ Vegfr-2↑ Nrp2↑ |
Lack of human trials | [183] |
| Treadmill running | Gradually increased to 25 m/min for 45 min, 5 days/week for 7 weeks supplemented with lactate | Male mice | Brain | Lactate accounted for some exercise-associated brain and liver bioenergetic infrastructure and bioenergetic-associated adaptations | PGC-1-related co-activator↑ Vegf-a↑ |
Lack of human trials | [184] |
| Treadmill running | Ten high-intensity exercise intervals of 4 min each and separated by 2 min of active rest at 25° incline, 5 days/week for 7 weeks | Wild-type mice HCAR1 KO mice (male and female) | Brain | HCAR1 played a key regulator of VEGF and angiogenesis | Hcar1↑ Vegf-a↑ Pgc-1↑ Capillary density↑ |
Lack of human trials | [185] |
| Wheel running | Voluntary running from 0.5 to 3.7 km/day for 2 weeks | Male rats | Brain | Resulted in VEGF-A promoter CpG DNA hypomethylation |
Bdnf↑ Igf-1↑ Fgf-2↑ Vegf-a↑ |
Lack of human trials | [186] |
| Treadmill running | 3 weeks of 30 min of running at a speed of 15 m/min per day for 6 days/week | Elderly female rats (22 months) | Brain | Induced angiogenic factors |
Vegf↑ Ang-1↑ Ang-2↑ Microvessel density ↑ |
Lack of human trials | [200] |
| Wheel running | 6 weeks of running | Elderly female mice (11–13 months) | Brain | Attenuated unhealthy brain aging markers, increased myelin markers, and improved vascular structure and function | Vegf↑ | Lack of human trials | [201] |
| Treadmill running | Gradually increased to 20 m/min for 20 min, 5 days/ week for 4 months | Elderly female and male rats (14 months) | Brain | Increased total capillary length and total surface area | Capillary length and surface area↑ | Lack of human trials | [202] |
| Swimming | Gradually increased to 60 min/day, 5 days/week for 8 weeks | Young male rats (4–6 months) and elderly male rats (23–34 months) | Brain | Improved cerebral microvascular changes and hypoperfusion associated with aging | Vegf ↑ eNos ↑ Flk-1 ↑ Capillary vascularity ↑ |
Lack of human trials | [203] |
| Wheel running | Starting from post-stroke day 7, 6 days/week for 21 days | Male mice with ischemic stroke | Brain | Facilitated recovery of motor function and promoted angiogenesis | Vegfr-2 ↑ doppel ↑ Pdgfrβ ↑ |
Lack of human trials | [207] |
| Treadmill running | 10 m/min, 5 days per week for 4 weeks | Male mice with MCAO | Brain | Promoted sensorimotor function, reduced infarct volume, decreased cell apoptosis, induced angiogenesis, and neurogenesis | MiR-126 in exosomes↑ BrdU+CD31+ cells ↑ |
Lack of human trials | [208] |
| Treadmill running | Moderate intensity: 60 per time, with speed set at 20 m/min; High-intensity: exercise duration was variable and the treadmill speed was gradually increased until the mice were exhausted, 3 times/week for 6 weeks | Male mice with chronically stressed | Brain | Prevented chronic stress-induced cognitive decline and increased vascular density | CD31+ cells↑ | Lack of human trials | [209] |
| Treadmill running | 25 m/min for 30 min, 5 days/week for 3 weeks | Male rats with MCAO | Brain | Reduced infarct volume, ameliorated sensorimotor function, activated astrocytes, and promoted angiogenesis | Midkine ↑ Bdnf ↑ |
Lack of human trials | [212] |
| Treadmill running | Gradually increased to 12 m/min at third day and persisted to 14th day | Male rats with MCAO | Brain | Improved the cerebral blood flow, reduced infarct volume, and promoted angiogenesis | CD31+ cells ↑ Tie-2 ↑ p-Akt ↑ |
Lack of human trials | [214] |
| Rota-rod and treadmill running | 30 min/day, 5 days/week to run on the Rota-rod (35 rpm = 8 m/min) or treadmill (8 or 20 m/min) for 2 weeks | Male rats with MCAO | Brain | Facilitated motor function, reduced the infarct volume, and induced striatal angiogenesis | Vessel density ↑ | Lack of human trials | [215] |
| Treadmill running | 20 m/min, 30 min/day, 5 days/week, and continued until 7 or 28 days | Male rats with MCAO | Brain | Attenuated the neurological deficit score, decreased infarct size, improved neural regeneration, and promoted angiogenesis | Caveolin-1 ↑ Vegf ↑ Vegfr-2/CD34 ↑ bFgf ↑ |
Lack of human trials | [217] |
| Wheel running | Gradually increased to 15 rev/min on the fourteenth day | Male rats with MCAO | Brain | Promoted neural function recovery and induced angiogenesis | CD31+cells↑ | Lack of human trials | [220] |
| Wheel running | 1 h/day, 5 days/week for 6 weeks | Diabetic db/db mice | Blood | Improved endothelial function and reduced body weight | Crp ↓ | Lack of human trials | [224] |
| Ladder climbing | A 1 meter high ladder inclined at 80° was used and exercised 6 repetitions/set, 3 sets/day, and 3 days/week for 4 weeks | Male diabetic db/db rats | Skeletal muscle and blood | Increased plasma NO levels | NO↑ Capillary-to-fiber ratio (unchanged) |
Lack of human trials | [225] |
| Treadmill running | Gradually increased to 30 min at a pace of 15 m/min, 5 days/week for 8 weeks | Male diabetic db/db mice | Heart | Improved cardiac angiogenic markers, decreased expression of inflammatory, improved insulin resistance, and endothelial dysfunction | eNos↑ Vegf-a↑ Hif-1α↑ |
Lack of human trials | [227] |
| Treadmill running | 17 m/min for 10 min on the first day with progressive increased every day (+5 min), reaching 30 min on the 5th day for 4 weeks | Male diabetic rats | Sciatic nerve | Increased neovascularization and altered sciatic structure | Vegf-a ↑ Capillary density ↑ Tsp-1 ↓ Nf-κb ↓ |
Lack of human trials | [229] |
| Treadmill running | 30 min/day, 5 days/week for 6 weeks | Male mice with obesity | Hindlimb tissue | Decreased perilymphatic inflammatory cell accumulation, improved lymphatic function |
Vegfr-3↑ Prox1↑ |
Lack of human trials | [231] |
Agpat1: 1-acylglycerol-3-phosphate O-acyltransferase 1; Bdnf: Brain-derived neurotrophic factor; COM: HIIT combined with strength training; Crp: C-reactive protein; CXCR4: C-X-C chemokine receptor type 4; DDAH1: Dimethylarginine dimethylaminohydrolase 1; Ece1: Endothelin-converting enzyme 1; EPCs: Endothelial progenitor cells; EPO: Erythropoietin; Errα: Estrogen-related receptor α; Fgf-2: Fibroblast growth factor 2; Flk-1: Fetal liver kinase 1; Fstl1: Follistatin-like protein 1; Gsk3β: Glycogen synthase kinase 3β; Hcar1: Hydroxy-carboxylic acid receptor 1; Hdm2: Human double minute-2; HIIT: High-intensity interval training; HIF-1α: Hypoxia-inducible factor-1α; Hsp70: Heat shock protein 70; Hsp90: Heat shock protein 90; Igf-1: Insulin-like growth factor-1; I/RI: Myocardial ischemia-reperfusion injury; JAK-2: Janus kinase-2; Lyve-1: Lymphatic vessel endothelial hyaluronan receptor-1; MACO: Middle cerebral artery occlusion; MI: Myocardial infarction; MMP-2: Matrix metalloproteinase-2; MMP-9: Matrix metalloproteinase-9; Nf-κb: Nuclear factor kappa-B; nNos: Neuronal nitric oxide synthase; NO: Nitric oxide; NOTCH-1: Notch (Drosophila) homolog 1 (translocation-associated); p-AKT: Phosphorylation of protein kinase B; p-AMPK: phosphorylation of adenosine 5′-monophosphate-activated protein kinase; p-eNOS: Phosphorylation of endothelial nitric oxide synthase; Pdgfrβ: Platelet-derived growth factor receptor β; PECAM-1: Platelet endothelial cell adhesion molecule; Pgc-1α: Peroxisome proliferator activated receptor-γ coactivator-1α; Pdpn: Podoplanin; Prox1: Prospero-related homeobox protein 1; RBCs: Red blood cells; Reln: extracellular protein Reelin; RM: Repetition maximum; SDF-1α: stromal derived factor-1α; Smad2/3: Mothers against DPP homolog 2 (Drosophila); Spp1: Secreted Phosphoprotein 1; Tgf-β: Transforming growth factor-β; Tie-2: Tyrosine kinase with Ig and EGF homology domain 2; TIMP-1: Tissue inhibitors of metalloproteinases-1; VEGF: Vascular endothelial growth factor; VEGFR-2: Vascular endothelial growth factor receptor 2; Vegf-c: Vascular endothelial growth factor C; Vegf-d: Vascular endothelial growth factor D; Vegfr-3: Vascular endothelial growth factor receptor 3; VO2max: Maximal oxygen uptake; VO2peak: Peak oxygen uptake; WBCs: White blood cells.
Current Problems and Prospects
Biomarkers of angiogenesis and lymphangiogenesis
Blood vessels play a vital role in maintaining overall health by performing several essential functions, including: delivering nutrients and oxygen to tissues and organs, supporting organ function, regulating blood pressure, safeguarding tissues and organs from damage, and facilitating the wound healing process.[232] Angiogenesis is the complex process by which new blood vessels form from existing capillaries or post-capillary venules. This multi-step process involves the breakdown of the vascular basement membrane, followed by the activation, proliferation, and migration of vascular endothelial cells. These cells then reorganize to form new blood vessels and vascular networks, ultimately establishing a functional microcirculatory system.[233] This complex procedure includes multiple components, including the production and release of numerous pro-angiogenic signals.[234] VEGF/vascular endothelial growth factor receptors (VEGF/VEGFRs) are the most important components and biomarkers in angiogenesis. It primarily targets vascular endothelial cells, promoting their proliferation and migration, and is involved in angiogenesis, embryonic development, and tumor progression.[235] In addition to VEGF/VEGFRs, other key factors and their receptors also play significant roles in angiogenesis. These include FGF and its receptors (FGFRs), which are crucial during embryonic development and wound healing.[236] Platelet-derived growth factor (PDGF) and its receptors (PDGFRs) facilitate vascular maturation by recruiting pericytes.[237] In addition, endothelial growth factor (EGF) and its receptors (EGFRs) stimulate signaling pathways that promote endothelial cell proliferation and differentiation. Furthermore, HIF-1α is essential for regulating angiogenesis in skeletal muscle and bone by controlling VEGF expression, NO availability, and a pathway activated by PGC-1α.[238,239] Apart from these, NOS,[240] MMP-2, MMP-9,[241] angiopoietin-1,[242] TGF-β,[243] IL-8, and monocyte chemoattractant protein 1 have also been found to be associated with the regulation of angiogenesis.[244] Angiogenesis is a vital process for tissue repair and regeneration under normal physiological conditions. However, imbalance in angiogenesis regulation can lead to excessive blood vessel growth, which subsequently lead to tumor growth, thus facilitating cancer progression.
Lymphatic vessels, composed of a single layer of endothelial cells, play a crucial role in maintaining physiological functions, including the reabsorption of fluids, transport of nutrients, and immune response regulation. However, pathological changes in these vessels can contribute to various diseases, including infections and tumors.[245] Lymphangiogenesis, the process of forming new lymphatic vessels, is a complex mechanism that involves the maturation and expansion of these vessels. This is vital for maintaining the body’s homeostasis, immune function, and metabolic balance. Similar to angiogenesis, lymphangiogenesis plays a critical role in various physiological functions, highlighting its importance in overall health.[246] This emphasizes the importance of understanding and targeting lymphangiogenesis in disease treatment. One key factor of lymphangiogenesis is VEGFR-3, a receptor activated by VEGF-C/D.[247] Studies have demonstrated the role of VEGFR-3, a receptor expressed by lymphatic endothelial cells, in promoting the formation of lymphatic vessel sprouts, even in the absence of a pre-existing outlet, thereby facilitating lymphangiogenesis. Furthermore, the VEGF-C/VEGFR-3 pathway plays a crucial role in responding to lymphatic obstruction by initiating remodeling and subsequent rounds of lymphangiogenesis, highlighting its importance in adaptive responses to lymphatic damage or disruption. Notably, recent research has identified specific markers, including Prox-1, Pdpn, and LYVE-1, which are upregulated during the formation of new lymphatic vessels, serving as indicators of lymphangiogenesis initiation.[248]
Current regimens and limitations for promoting angiogenesis and lymphangiogenesis
Many methods have been used to enhance angiogenesis at both the preclinical and clinical levels, and these have been summarized in several reviews, such as VEGF, FGF and their genes, peripheral blood-derived EPCs or bone marrow-derived cells in the heart.[249] Some cell therapies, including stem cells, have been tested in clinical trials for the treatment of ischemic diseases.[250] In vitro and in vivo studies on angiogenic factors are conducted to explore their therapeutic potential in promoting cerebrovascular formation, such as VEGF, IGF, BDGF, FGF, PDGF, epidermal growth factor (EFG), tumor necrosis factor-alpha/beta (TNF-α/β), netrin, IL-1β/6/8, Ang1/2, αVβ3, Noth, homeobox D3/A5, MMPs, and tissue inhibitor.[251] All these cell therapies, cytokine therapies, and gene therapies that have been demonstrated to be successful at the preclinical have failed in the cardiovascular system. Notably, in the muscular system, only bone marrow autograft for limb ischemia has advanced to phase III clinical trials. These indicate that the effects of exogenous methods for promoting angiogenesis in different organs are not satisfactory in humans. Some new attempts might need to consider the specific induction of angiogenesis in specific organs, such as cocktail therapy (combining multiple angiogenic factors or cells), and targeted drug delivery (such as through the blood–brain barrier). In addition, some new substances possess therapeutic potential, such as Amlodipine, alpha-Asarone, irisin,[252,253,254] microRNAs,[255] EVs,[256,257] cells,[258,259] and nanocarrier-based delivery systems[260,261] have been used to promote angipgensis. However, these methods have yet to be further tested in humans. Dysregulated angiogenesis affects both normal physiological processes and various diseases, whether due to excessive or inadequate blood vessel formation. It is worth noting that artificially elevating tissue levels of VEGF or FGF may result in adverse effects such as embryonic cardiovascular malformations/embryonic death, thrombocytopenia, and kidney disease.[262,263] Exercise as an endogenous stimulus for angiogenesis and lymphangiogenetic shows significant promise for the management of a range of diseases. It may have a positive effect to some extent through precise regulation of the body’s own systems. Taking an example, the FoxO transcription factor exerts a suppressive effect on the development of new blood vessels in skeletal muscle during exercise.[264] There is an intricate coordination in the protein reactions of both pro-angiogenic and anti-angiogenic factors after muscle capillary adaptations induced by exercise. Furthermore, the training-induced adaptations also influenced the basal expression of these factors and immediate motor reactions.[265] Chronic exercise training led to the development of telangiectasia, and notably, capillary proliferation persisted despite prolonged training duration. However, baseline expression levels of VEGF and TSP-1 exhibited a discordant relationship with exercise-induced muscle capillary expansion. This paradox suggests a negative feedback mechanism that modulates excessive capillary dilation, thereby regulating angiogenic responses to exercise.[266] Exercise-induced angiogenesis is temporally regulated, allowing the body to modulate vascular development and maintain homeostasis by preventing excessive activation.
Researchers have identified potential methods and targets to promote lymphangiogenesis, despite the lack of available drugs. For instance, CGS21680, an adenosine A2A receptor agonist, has been shown to promote lymphatic endothelial cell growth and increase lymphatic density by activating VEGFR-2 signaling, leading to improved blood pressure regulation and sodium clearance in mice on a high-salt diet.[267] CAPW-1 (an arabinogalactan) and Andrographolide promote proliferation and migration of lymphatic endothelial cells, thus enhancing lymphatic drainage and alleviating secondary lymphedema.[268,269] Hydrogen sulfide donor enhances lymphoendothelial cell proliferation and tube formation, stimulates Akt/eNOS signaling, promotes NO production, and suppresses ROS generation.[270] Piper retrofractum extract and piperine have been found to promote the growth and development of human dermal lymphatic endothelial cells by inducing the phosphorylation of Akt and ERK proteins.[271] Some exogenous stimuli may also promote lymphangiogenesis, such as radiofrequency irradiation increased HSP90/BRAF/mitogen-activated protein kinase (MEK)/ERK expression, decrease tyrosinase activity, and enhance skin lymphangiogenesis.[272] Low-dose cadmium enhances alkali burn-induced corneal lymphangiogenesis by inducing phosphorylation of signal transducer and activator of transcription 3 (STAT3), and enhancing the expression of VEGFR-3 protein.[273] H2O2-induced VEGF-A and VEGF-C secretion in fibroblasts promotes lymphatic endothelial cell (LEC) recruitment, tube formation and increase monolayer permeability, thus enhancing wound healing.[274] In addition, several proteins and cell-derived substances have been found to promote lymphangiogenesis in vitro and in vivo, such as cartilage oligomeric matrix protein fused Ang-1, EphrinB2, conjugated bile acids, hypoxia-conditioned adipose-derived mesenchymal stem cells-derived EVs, M2b macrophages, and M2 macrophage-derived exosomes in different organs.[275,276,277,278,279,280] Although various approaches have shown potential in promoting lymphangiogenesis, substantial gaps in understanding persist. The mechanisms of action, absorption, and distribution profiles of these methods, such as CGS21680 and piperine, are poorly understood. Moreover, concerns regarding their potential toxicity, optimal dosing, and storage protocols warrant further investigation. Excessive lymphatic vessel formation has been implicated in tumor progression and metastasis, underscoring the need for targeted and controlled lymphangiogenesis strategies.[281,282,283,284] These suggest that inappropriate methods leading to excessive lymphangiogenesis may have adverse consequences. Exercise-induced lymphangiogenesis may provide a therapeutic avenue for disease prevention by enhancing endogenous homeostasis, paralleling the well-documented angiogenic benefits of exercise. However, further research is necessary to fully understand the mechanisms, effects, and potential side effects of exercise-induced lymphangiogenesis across various organs, beyond its currently documented impacts on the heart and lymphatic endothelial cells.
Factors influencing exercise-stimulated angiogenesis and lymphangiogenesis
The effects and potential mechanisms of various exercises on angiogenesis and lymphangiogenesis remain unclear at present. Nevertheless, although aerobic exercise and anaerobic exercise have distinct focuses on the effects on different organs, both can stimulate angiogenesis. First of all, in the circulation, aerobic exercise such as running, cycling, and climbing increased the number of PBMCs,[55] EPCs,[71] and raised the levels of SIRT1 and VEGF[72] in the blood. Although hypoxic or anaerobic exercises not only enhanced the levels of EPCs and VEGF but also improved MMP-9 (in hypoxic exercise)[43] and VEGFR-2 and CD34 (BFRE),[45] as well as HIF-1α (in sprint and resistance),[46] and increased the number of CD34+ cells (in sprint)[53] in the circulation. Chronic mixed chronic mixed exercise upregulates the expression of miR-208b and miR-221, potentially facilitating angiogenesis.[57] Aerobic exercise (e.g., swimming, running) enhances cardiac expression of angiogenic factors, including MMP-9,[86] DDAH1,[88] VEGF,[89] eNOS,[227] HSP70,[105] HIF-1α,[120] and VEGF-A.[227] Moreover, aerobic exercise upregulates specific microRNAs, notably miR-126 and miR-210.[90] In addition to VEGF, anaerobic exercises like HIIT could also enhance the expression of FGF-2 in the heart.[110] The combined aerobic and anaerobic exercise regimen effectively augmented cardiac HIF-1α and VEGF expression.[85] In the muscular system, some of the effects resulting from aerobic and anaerobic exercise were similar. Notably, significantly increased levels of PGC-1α, VEGF, and eNOS were found in aerobic exercise (running),[139] anaerobic exercise HIIT, strength, resistance, hypoxic or combined training, and flexibility exercise.[171] In the muscles, anaerobic exercise was more likely to specifically enhance HIF-1α,[141] VEGFR-2,[141] and iNOS[141] compared with aerobic exercise. Aerobic exercise selectively increased VEGF-A, CD34,[144] nNOS,[152] PECAM-1, HDM2,[173] and EVs containing specific miRNAs.[154] Aerobic exercise (running and swimming) mainly boosted VEGF,[183] VEGFR-2,[183] eNOS,[183] and EVs-containing miR-126,[183] whereas anaerobic exercise (HIIT) specifically upregulated HCAR1[183] in the brain. Both aerobic and anaerobic studies have discovered upregulated VEGF-A.[183] Given the scarcity of research on exercise-induced lymphangiogenesis, aerobic exercise has been shown to upregulate key lymphangiogenic biomarkers, including VEGFR-3, Pdpn, LYVE-1, VEGF-C, and VEGF-D[231] [Figure 1]. Overall, aerobic exercise is more prone to long-term metabolic adaptation, maintenance of vascular homeostasis (such as eNOS, PGC-1α), and has an impact on the lymphatic system. Anaerobic exercise is more inclined to acute hypoxia response and rapid vascular remodeling (such as HIF-1α, iNOS), and enhances the short-term adaptability of muscles and hearts. Combined training leverages the benefits of both aerobic and anaerobic exercise, synergistically enhancing cardiac HIF-1α and VEGF expression to promote comprehensive vascular health. Specifically, aerobic exercise drives metabolic adaptation and vascular homeostasis, whereas anaerobic exercise induces hypoxic stress and rapid remodeling, with combined exercise yielding a synergistic effect.
In addition, factors influencing exercise-induced angiogenesis and lymphangiogenesis, such as exercise type and individual characteristics, are crucial to consider for optimizing vascular adaptations and promoting healthy aging. The type and variety of physical activities, such as aerobic, strength, endurance, and combined training, can significantly influence the induction of angiogenesis and lymphangiogenesis. MiR-210 is an microRNA that relates to cell apootosis and angiogenesis which is regulated in the adaptation process induced by exercise. The aerobic exercise, such as swimming, could elevate miR-210 levels and promote cardiomyocyte proliferation, thus protecting against I/RI.[285] But some studies showed that miR-210 levels remained unaffected by acute and exhaustive exercise.[286,287] Acute exercise sessions yield inconsistent results regarding VEGF and MMP levels, with some studies showing increased MMP-9, but no significant changes in VEGF and MMP-2.[288] The differences in these findings between studies might be attributed to different exercise types. Numerous researches have shown that physical activity upregulated VEGF levels in the bloodstream, others have reported little changes or even decreased levels.[289,290] Notably, research comparing exercise intensities has yielded disparate findings, suggesting that exercise intensity is an important factor affecting angiogenesis. Low-intensity exercise protocols, such as step tests, resulted in decreased or unchanged circulating VEGF levels. In contrast, high-intensity exercise[291] and high amount interval exercise[292] elicited significant increases in VEGF. HIIT induced significant changes in acid–base balance and elevates circulating VEGF levels in healthy individuals. In contrast, low-intensity continuous training failed to elicit these effects.[293] This indicates that the level of exercise intensity is a key factor in regulating VEGF reactions. A study showed male participants were subjected to ergometer cycling with 4 weeks of intense intermittent training. Reaching this did not result in a higher level of capillarization within the muscle.[294] Twelve male triathletes/cyclists who underwent three distinct training regimens indicated that HIIT and high-intensity continuous training resulted in a temporary rise in VEGF levels and hepatocyte growth factor in circulating blood, while high-volume training resulted in decreased levels of these growth factors.[295] This also suggested that varying exercise intensities might have distinct effects on angiogenesis. A total of 63 male mice were subjected to treadmill training at gradually increasing intensities. The levels of HIF-1α,VEGFR-1/2, and iNOS varied based on exercise intensity. Specifically, mild-intensity exercise led to an increase in HIF-1α and VEGFR-1 expression, while increased exercise intensities led to a progressive enhancement of VEGFR-2 levels.[296] VO2max, or maximal oxygen uptake, serves as a key indicator of exercise intensity and cardiorespiratory fitness. Several studies have specifically used VO2max as a metric to quantify exercise intensity, providing a precise measure of aerobic capacity. Some exercises could lead to the development of angiogenesis, but this outcome was influenced by the levels of exercise. Studies have found an increase in capillarization when training over 60% of VO2max, while no effect on capillarization has been observed with training below 45% of VO2max intensity.[297,298,299] It was of note that long-term hypoxic exercise (8-week treadmill running) significantly attenuated gene expression of VEGF and its receptors Flt-1.[300] Angiogenesis-related factors were influenced by the individual’s training status. Untrained individuals showed comparable rises in PGC-1α mRNA levels following both speed endurance training and endurance training.[301] However, conflicting findings have been reported, with one study showing no significant changes in muscle PGC-1α mRNA after 60-min endurance exercise at 60% VO2max.[302] In contrast, 60 min of cycling at 60% VO2max increased muscle VEGF mRNA levels in untrained individuals.[297] The low-intensity knee-extensor exercise (3 h) revealed a more pronounced increase in VEGF mRNA expression in the untrained legs compared to the trained legs.[303] These results emphasize the impact of training level on exercise-induced angiogenesis. Revealing these different results emphasizes the intricate nature of exercise-induced angiogenesis and the significance of taking individual traits into account. Studies have reported no significant changes in lymphatic capillary adaptation or lymphangiogenic markers (VEGF-C and VEGF-D) in human skeletal muscle following acute exercise or in mouse skeletal muscle during endurance training.[304,305] One study found that road cyclist participants subjected to immediate exercise over a 9-day period for 45 days did not impact VEGF-C and D, suggesting that mechanical stimuli might not be the main factor driving lymphangiogenetic responses. The reduction in the density of lymphatic capillaries expressing LYVE-1 was interesting, as it went against the expected functional role of lymphatic vessels within the skeletal muscle of humans.[306] Dogs subjected to treadmill exercise at varying speeds, ranging from 0 to 10 mph and back to 0 mph, exhibited an increase in lymphatic flow in the thoracic duct. This increase was found to be associated with higher levels of exercise intensity. Notably, higher treadmill speeds elicited even greater lymph flow responses.[307] These findings suggest that exercise intensity positively influences lymphatic circulation, facilitating enhanced leukocyte mobilization through the lymphatic system. Exercise-induced improvements in lymphatic function may be attributed to increased lymph fluid circulation and heightened contraction and relaxation frequencies of lymphatic vessels. Ultimately, this may lead to augmented detoxification capabilities and immune function within the lymphatic system. The differences in outcomes of exercise-induced angiogenesis and lymphangiogenesis have been summarized in Table 2.
Table 2.
Summary of research on factors influencing exercise-induced angiogenesis and lymphangiogenesis.
| Type | Protocol | Subject | Tissue | Results | Reference |
|---|---|---|---|---|---|
| Rowing | Daily rowing at a 5 km distance = (1 to 3 h) at low stroke rates (20 to 24 strokes per minute) for 90 days. | Males | Plasma | No miR-210 response to the exercise | [286] |
| Cycling | Starting at 50W and gradually increased by lasting 3 min | Males and females with coronary artery disease | Blood | No changes in VEGF and MMP-2 levels | [288] |
| Cycling | Increased progressively every 3 min in steps of 25 W, beginning at 25 W | Patients with coronary artery disease | Blood | No changes in VEGF levels in nonischemic patients and healthy subjects | [289] |
| Rowing and sprint | Rowing for 10 min and did 2 to 3 sprints of 5 to 6 strokes | Male and female competitive rowers | Blood | Increased VEGF level | [291] |
| Cycling | Four training sessions weekly under normoxic and hypoxic with or without vibrations; each session lasted 90 min and consisted of a 10-min warmup followed by 10 intervals of 3-min high load and 5 min recovery | Males | Blood | Increased VEGF level | [292] |
| Cycling | Short-term high-intensity training lasted 42 min followed by 4 × 30 s all-out exercise bouts for 2 weeks; high-volume endurance training consisted of a constant load exercise for 1 h at 50% peak power output at the 3rd week | Males | Blood | Low intensity caused an insufficient stimulus for VEGF secretion | [293] |
| Cycling | 4 week period of conditioning by moderate-intensity ergometer cycling for 60 min three times/week and 24 bouts of intense intermittent cycling with 1 min for three times/week for 4 weeks | Males | Muscle | Decreased VEGF level | [294] |
| Cycling | High-volume training (130 min at 55% PPO); high intensity training: (1) 4×4 min at 95% PPO; (2) 4×30 s all-out | Male triathletes/cyclists | Blood | High-volume training decreased VEGF level | [295] |
| Treadmill running | 5 days/week on a rotating treadmill for 15, 30, and 45 days | Male mice | Heart | Mild-intensity exercise increased Hif-1α and Vegfr-1 levels while increased exercise intensities resulted in high levels of Vegfr-2 | [296] |
| Cycling | 13 training sessions and each session lasted 60 min, 3 times/week for 4 weeks | Males | Skeletal muscle | 50% VO2max of acute and aerobic exercise did not induce increased VEGF level while 60% VO2max of cycling increased VEGF mRNA level in untrained subjects | [297] |
| One-legged knee extensor | 150% of leg VO2max for 1 h , 3 times/week for 2 weeks, 3 times/week for the next 2 weeks and 5 times/week for the last 3 weeks; 1 min bouts at 90% of leg VO2max, 3 times/week for 6 weeks | Males | Skeletal muscle | >90% VO2max of intense training increased in capillary-to-fiber ratio and Ki67+ ECs | [298] |
| Skiing with a backpack | 30 km of skiing with backpacks on (25 kg), 6 days/week for 8 weeks and a subsequent period of detraining for 33 weeks | Males | Skeletal muscle | 45% VO2max of endurance training did not induce an adaptive response and angiogenesis in the leg muscles | [299] |
| Treadmill running | 1 h at 18 m/min with 10° incline in normoxia and chronic hypoxia for 8 weeks | Rats | Skeletal muscle | Attenuated gene expression of Vegf and its receptors Flt-1 | [300] |
| Cycling | 60 min at 74 ± 2% VO2peak for two bouts and at least 7 days with or without carbohydrate supplement | Males | Skeletal muscle | No change in PGC-1α mRNA level | [302] |
| One-legged knee extensor | 70% or 110% of the maximal workload for 5 days/week for 4 weeks | Males | Skeletal muscle | Increased VEGF mRNA level in untrained legs compared to the trained legs | [303] |
| Unilateral maximal drop jumps | 100 jumps at a rate of one every 5 s (50% of individual maximum) until exhaustion | Males | Skeletal muscle | No changes in VEGF-A, B, C, D, and HIF-1α levels | [304] |
| Treadmill running | 21 m/min, 1 h/day for 5 days/week | Male diabetic mice | Skeletal muscle | No changes in Vegf-c, Vegf-d, and Vegfr-3 levels | [305] |
| Cycling | Five consecutive 9-day periods for 45 days | Male amateur cyclists | Skeletal muscle | No changes in VEGF-C and VEGF-D level, decreased LYVE-1 level | [306] |
| Treadmill running | Increased 0 to 1.5, 3, 4, 5, 6, 7, 8, 9, and 10 mph, and the speed was reversed and continued to decline | Male and female dogs | Thoracic duct | Enhanced lymph flow | [307] |
ECs: Endothelial cells; Hif-1α: Hypoxia-inducible factor-1α; LYVE-1: Lymphatic vessel endothelial hyaluronan receptor-1; MMP-2: Matrix metalloproteinase-2; PPO: Peak power output; VEGF: Vascular endothelial growth factor; VEGF-C: Vascular endothelial growth factor C; VEGF-D: Vascular endothelial growth factor D; Vegfr-1: Vascular endothelial growth factor receptor 1; Vegfr-2: Vascular endothelial growth factor receptor 2; VO2max: Maximal oxygen uptake; VO2peak: Peak oxygen uptake.
Potential risks of exercise
A large amount of evidence suggests that excessive exercise can lead to damage in multiple organs and systems. Exercise-induced myocardial injury refers to the adverse effects on the heart caused by high-intensity or inappropriate exercise. Its clinical manifestations include changes in cardiac morphology, abnormal myocardial injury markers, exercise-induced arrhythmia, syncope, and even sudden death.[308] Excessive endurance exercises, such as marathons and triathlons, might lead to increased, myocardial fibrosis, arteriosclerosis, and other adverse consequences, thereby enhancing the risk of arrhythmia and cardiovascular diseases.[309] Endurance athletes might encounter right heart failure (HF) and pulmonary hypertension under long-term and high-intensity training. Excessive exercise has been associated with an increased risk of arrhythmia. Notably, female athletes may be more susceptible to cardiovascular disease after menopause due to decreased estrogen levels. Studies in animal models have demonstrated that excessive exercise can lead to myocardial fibrosis and arrhythmia, suggesting a potential correlation between increased exercise intensity and cardiac damage.[310] Shoulder injuries are highly common among athletes engaged in shoulder-load sports, such as tennis, handball, volleyball, swimming, and other activities. Excessive use of the shoulders led to shoulder stiffness, thereby increasing the risk of shoulder injuries.[311] For individuals with hereditary arrhythmia-induced cardiomyopathy, exercise might exacerbate right ventricular dysfunction, resulting in cardiomyocyte apoptosis, and causing arrhythmia and even sudden death.[312] Due to exercise-induced rhabdomyolysis and metabolic disorders, patients with obsessive-compulsive disorder have experienced serious complications such as bradycardia, hypothermia, and hypoglycemia.[313] Blood flow restriction training may lead to the accumulation of metabolic waste products and cellular swelling. In addition, this type of training can induce oxidative stress responses, resulting in the generation of ROS and their derivatives, which can cause cellular damage.[314] Muscle injuries resulting from exercise are frequently caused by high-intensity or maladjusted eccentric movements. Their features include damage to muscle segments, cytoskeletons, and membranes, as well as the disruption of the myoplasmic reticulum membrane, which gives rise to calcium ion homeostasis disorders and compromised excitation–contraction coupling. These alterations not only lead to a decrease in muscle strength and impaired motor ability but are also accompanied by inflammatory responses, the disturbance of muscle ultrastructure, the impairment of excitation–contraction coupling, and the degradation of muscle proteins.[311,315] Injuries resulting from excessive exercise or inadequate recovery may heighten the risk of injury, especially among the elderly. Compared to young people, the elderly were more prone to muscle damage and needed more time to recover. Following completion of a 30–55 km walk, elderly subjects exhibited elevated levels of Troponin I, a well-established biomarker of cardiac damage. Notably, elevated Troponin I levels are recognized as early predictors of mortality and cardiovascular events.[316] High-intensity exercise is generally not recommended for elderly individuals with physical frailty or advanced illness, as it may precipitate cardiovascular stress, musculoskeletal injury, and excessive fatigue.[317,318] However, for individuals with mild to moderate frailty, supervised interval training, characterized by short periods of high-intensity exercise interspersed with rest periods, may be a feasible and potentially beneficial approach.[319] High-intensity exercise may exacerbate cardiovascular burden in certain populations, such as those with HF, and the risk of falls/fractures in individuals with osteoporosis and sarcopenia. Furthermore, it may worsen symptoms in patients with chronic obstructive pulmonary disease, such as dyspnea, and exacerbate fatigue in patients with cancer cachexia. Notably, there is currently no direct evidence to suggest that exercise increases the recurrence of cancers characterized by high vascularization.[320] However, for cancers with characteristics similar to hemangiomas or certain sarcomas, which may be prone to bleeding or other complications with increased physical stress, it is prudent to avoid strenuous exercise.
Exercise protocols and recommendations for the patients and elderly
As the exercise plans corresponding to various diseases may differ, here we summarize the recommended exercise plans related to the aforementioned diseases. It is suggested that patients with hypertension undertake aerobic exercise (cycling) 3 to 5 times a week, with each session lasting 30 to 60 min, at 75% of VO2max or 60% to 70% of the maximum heart rate. Meanwhile, they should perform 10 min of cycling for recovery after exercise and maintain this for 12 weeks.[297] Patients with thrombosis should initiate mobilization as early as feasible during the acute stage. For chronic management, long-term patients can engage in comprehensive exercise programs, including aerobic exercise, resistance training, and flexibility exercise for 6 to 12 months. Specifically, the recommended regimen includes: aerobic exercise 60 to 120 min per week, strength training 3 to 4 sessions per week, and flexibility exercises 7 sessions per week, at moderate intensity.[321,322] The exercise rehabilitation program should include a combination of aerobic exercise and resistance training for at least 3 to 6 months, with an exercise frequency of 3 to 5 times a week and each session lasting 20 to 90 min. The intensity of exercise should be controlled at 50% to 90% of the maximum or peak heart rate, or 50% to 95% of aerobic capacity. HIIT (20–45 min each time) can be introduced in the later stage, including 4 to 8 intermittent alternating exercise cycles of high and low intensities.[323,324] Patients with chronic HF can undertake single-leg knee extension exercises, HIIT, moderate to low-intensity aerobic exercise, or strength training (3–5 times a week, with an intensity of 50–80% VO2peak).[297,325] Patients with muscle atrophy are recommended to engage in a multimodal exercise program consisting of 2–3 sessions per week at an intensity of 70–80% of one-repetition maximum (1RM), in combination with balance and aerobic exercise. It is recommended that balance training be carried out 3 to 4 sessions per week with each session lasting 15 to 20 min. Aerobic exercise is suggested to be performed 3 to 4 sessions per week, each for 30 to 45 min, and the intensity should be controlled at a moderate level (the heart rate being approximately 60% to 70% of the maximum heart rate). This structured exercise regimen should be maintained for a minimum duration of 12 weeks to optimize therapeutic benefits.[326,327] Patients with stroke are recommended to undertake moderate-intensity aerobic exercise (60–80% of the maximum heart rate), combined with resistance and balance training (3–5 times a week for 12–24 weeks).[328,329] Diabetic patients should combine aerobic exercise (60–80% of the maximum heart rate), resistance (8–12 repetitions per group), and HIIT (3–5 times per week).[330,331] Obese patients are advised to engage in 150-420 min/week of moderate-intensity aerobic exercise such as walking and swimming, and resistance training should be conducted at least twice per week.[332,333]
The World Health Organization (WHO) suggests that older adults should engage in at least 5 min of high-intensity aerobic exercise and 150 min of moderate-intensity aerobic exercise per week regarding the intensity and frequency of exercise. People of all ages, including the elderly, should regularly engage in muscle strength training.[334] In addition, the American College of Sports Medicine Guidelines recommend that older adults undertake exercises encompassing aerobic, muscle strengthening, endurance, flexibility, and neuromotor exercises above the frequency and moderate intensity of at least two days per week.[335] Other programs related to exercise for the elderly have also been proposed. For elderly people suffering from depression, a 12-week, twice-weekly, 45-min low-intensity aquatic exercise program significantly decreased depression and anxiety scores among depressed older adults, while enhancing dynamic/static balance and flexibility.[336] For cognitive health, aerobic exercise (lasting more than 13 weeks) enhanced working memory and cognitive flexibility of the elderly.[337] In older adults with functional limitations, exercises such as transfers, walking, and stepping have been shown to significantly enhance the mobility in this population.[338] Furthermore, among hospitalized older adults, low-intensity walking (25–50 min per day) has been associated with improved functional capacity and reduced adverse events, with optimal benefits observed at approximately 40 min of moderate-intensity activity per day.[339] The elderly should undertake a comprehensive exercise regimen that includes aerobic, strength, balance, and flexibility training to maintain and enhance their functional capabilities. Progressive resistance training plays a vital role in maintaining or improving functional ability, especially in vulnerable populations such as frail elderly individuals, those with sarcopenia or osteoporosis, and patients in acute care or long-term care facilities.[340] Therefore, for the elderly, long-term low-intensity, moderate-intensity, or high-intensity aerobic exercise (at least 5 min based on one’s personal endurance) combined with strength training and other comprehensive exercises at least twice a week was beneficial for the elderly. However, to stimulate angiogenesis and lymphangiogenesis for anti-aging and disease prevention, research suggested that combined exercises, such as HIIT, resistance training, and endurance exercises exceeding 60% of VO2max, can be effective. However, it is crucial to personalize exercise programs, especially for older adults with underlying medical conditions, to ensure safety and efficacy.
Future research directions
Regular exercise is fundamental to maintaining optimal physical and mental health. Exercise promotes musculoskeletal growth and development,[341,342] and enhances the function of various physiological systems, including the cardiovascular, cerebrovascular, respiratory, digestive, and excretory systems. This, in turn, contributes to improved physical fitness, delayed aging, and enhanced disease resistance.[343,344,345,346] Despite the established benefits of exercise on aging, significant knowledge gaps persist regarding the optimal exercise modalities for mitigating age-related changes. Specifically, the most effective type, duration, and intensity of exercise for rapid and sustained anti-aging effects remain unclear. Further research is needed to elucidate the biological mechanisms underlying exercise-induced benefits and to determine the duration of these effects after training cessation. Moreover, the development of tailored exercise strategies for older adults is hindered by limited evidence, particularly at the molecular level. Standardized evaluation methods are also lacking, which impedes the development of anti-aging therapeutics. Investigating the regulation of angiogenesis and lymphangiogenesis may provide insights into novel approaches to slow aging. Furthermore, the combination of exercise and medication could offer a new therapeutic opportunity. For example, HIIT combined with L-lactate injections activated vascular endothelial cells and promoted neovascularization.[343,344,345,346] Combining exercise with pharmacological interventions, such as metformin, has been shown to yield greater efficacy in improving glucose metabolism than metformin alone, particularly in patients with type 2 diabetes.[331] In addition, GLP-1 receptor agonists (e.g., liraglutide) paired with regular exercise (e.g., 2 h of moderate-intensity exercise per week) may enhance the durability of weight loss outcomes.[347] Furthermore, whole-body vibration therapy in conjunction with exercise has demonstrated superior benefits over exercise alone in enhancing motor cortex excitability, quadriceps strength, and functional capacity in athletes following anterior cruciate ligament reconstruction.[348] Therefore, these findings suggest that integrating exercise with pharmacological or adjunctive therapies may yield additive benefits, particularly for individuals with chronic conditions and older adults.
Conclusion
In conclusion, exercise-induced angiogenesis and lymphangiogenesis show promise for promoting health, anti-aging, and disease resistance by enhancing vascular function and physiological resilience. Further research is warranted to elucidate the underlying molecular mechanisms, particularly lymphangiogenesis, and to explore therapeutic applications. Nonetheless, the existing evidence underscores the importance of incorporating exercise into one’s lifestyle, which can yield numerous benefits, including improved cardiovascular health and enhanced overall well-being, regardless of age or starting point.
Funding
This work was supported by the grants from the National Key Research and Development Program of China Grant (No. 2022YFA1104500), National Natural Science Foundation of China (Nos. 82020108002, and 82225005), the and Science and Technology Commission of Shanghai Municipality (Nos. 23410750100, 20DZ2255400, and 21XD1421300), the “Dawn” Program of Shanghai Education Commission (No. 19SG34).
Conflicts of interest
None.
Footnotes
Jizong Jiang, Yongjun Zheng, and Rui Wang contributed equally to this work.
How to cite this article: Jiang JZ, Zheng YJ, Wang R, Yang H, Zang SH, Chatterjee E, Li GP, Cretoiu D, Zhao CM, Xiao JJ. Exercise-induced angiogenesis and lymphangiogenesis: A potential therapeutic tool to fight aging and disease. Chin Med J 2025;138:2552–2587. doi: 10.1097/CM9.0000000000003831
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