Exploring the application of shear stress in erectile dysfunction

Abstract

Erectile dysfunction (ED) is a prevalent disorder in men and has a negative impact on quality of life. Recent studies have demonstrated that shear stress plays a critical role in modulating vascular endothelial function. Shear stress is categorized into physiological (e.g., laminar) and pathological (e.g., low shear or oscillatory) shear stress. This study reviewed current literatures on the relationship between share stress and ED, aiming to advance strategies for enhancing erectile function. Physiological shear stress increases the production of nitric oxide by activating endothelial nitric oxide synthase, thereby maintaining vascular homeostasis and erectile function. However, pathological shear stress exacerbates inflammation and oxidative stress, inducing endothelial dysfunction and ED. Shear stress also regulates gene expression, cell behavior, and signaling pathways in endothelial cells through multiple mechanisms, ultimately influencing erectile function. Studies indicate that exercise improves endothelial function and mitigates oxidative stress and inflammation by inducing shear stress, thereby offering novel therapeutic avenues for ED. Future research should focus on elucidating shear stress-mediating regulatory mechanisms, and developing diagnostic and therapeutic strategies to improve clinical outcomes in patients with ED.

INTRODUCTION

Erectile dysfunction (ED) is a highly prevalent condition in men and is associated with psychological distress and emotional issues that significantly impair life quality.1 Traditional perspectives on ED have focused primarily on vascular, neurological, and hormonal factors. However, recent advances in our understanding of hemodynamic shear stress have highlighted more intricate mechanisms underlying erectile function. Shear stress affects a series of cellular events, including production of nitric oxide (NO), inflammation, and oxidative stress, playing a key role in maintenance of endothelial homeostasis.2 These shear stress-induced pathological changes in the phenotype of the endothelium have a profound impact on the occurrence and progression of vascular diseases, such as atherosclerosis.3 This review examines the research landscape of shear stress in ED, emphasizing its potential to enhance our understanding of the pathology involved and identify novel diagnostic and therapeutic strategies.

The PubMed database was searched for relevant studies from 2000 to 2025 using the following search terms: “shear stress” OR “erectile dysfunction”, “shear stress” AND “inflammation”, “shear stress” AND “nitric oxide”, “shear stress” AND “oxidative stress”, “shear stress” AND “cell proliferation”, “shear stress” AND “cell differentiation”, “shear stress” AND “cell migration”, “shear stress” AND “cell apoptosis”, “shear stress” AND “cell metabolism”, and “shear stress” AND “exercise”. The search identified 406 potentially relevant articles. After 327 exclusions, 79 articles were selected for review. A flow diagram summarizing the article selection process is provided in Figure 1.

Figure 1.

The flow diagram that depicts the flow of information through the different phases of this review.

PHYSIOLOGY OF PENILE ERECTION

Release of NO is the primary mechanism initiating penile erection under normal physiological conditions. NO is synthesized by both cavernous nerve terminals and vascular endothelium. It is released from cavernous nerve terminals in response to activation of neuronal nitric oxide synthase, which in turn is activated by transduction of sexual stimulation signals from the hypothalamus to cholinergic and non-cholinergic nerve fibers. The latter involves increased vascular blood flow, which stimulates endothelial cells (ECs), causing endothelial nitric oxide synthase (eNOS)-activated release of NO. Subsequently, increased NO diffuses to the smooth muscle in the nearby corpus cavernosum, activating the cyclic guanosine monophosphate (cGMP) pathway, reducing intracellular calcium ion levels, and promoting relaxation of smooth muscle. The inflow of blood increases in response to smooth muscle relaxation and arterial vasodilation, while venous outflow is mechanically restricted by the engorged corpus cavernosum. These processes culminate in erection.4,5

Phosphodiesterase type 5 plays an important role in the process of erection. Consumption of cGMP can be decreased by a phosphodiesterase type 5 inhibitor, which helps to prolong the activity of cGMP and enhance erectile function. Moreover, there are alternative pathways associated with erectile regulation, including mechanisms mediated by cAMP, carbon monoxide, and hydrogen sulfide.4,6 The restricted ability of the endothelium to synthesize NO compromises normal erectile function in the presence of pathological conditions, such as inflammation, oxidative stress, and apoptosis.

SHEAR STRESS

In hemodynamics, shear stress (τ) refers to the tangential force exerted by the friction of blood flow on vascular endothelium, which is calculated as τ = 4ηQ/πr³ (where η = blood viscosity, Q = flow rate, and r = vessel radius).7 Shear stress can be categorized into physiological and pathological types. Physiological shear stress is typically in the range of 10–70 dyne cm⁻² and is usually laminar shear stress (LSS), which is characterized by smooth and unidirectional blood flow in straight vessel sections. This type of shear stress can protect the vascular endothelium and help maintain both vascular homeostasis and erectile function. Pathological shear stress arises in pathological conditions that are accompanied by abnormal blood flow patterns or changes in vascular structure and includes low and oscillatory shear stress (OSS). Low shear stress is defined as a value <10 dyne cm⁻², while OSS is characterized by turbulent, variable blood flow. OSS is often found in vessel branches, stenoses, and bends and is associated with endothelial dysfunction and other vascular abnormalities.8 Shear stress influences many physiological and pathological processes in the body. Acting as a mechanical signal, it activates mechanosensors, initiates signal transduction, and has various biological effects, including inflammation, oxidative stress, and production of NO. These effects are closely associated with ED, making shear stress an important factor in its pathogenesis.

SHEAR STRESS AND INFLAMMATION

Inflammation is a pathological hallmark of and an independent risk factor for numerous diseases, including ED. Inflammatory processes impair erectile function through mechanisms such as anatomical alterations, cytokine activity, psychological stress, and neuroendocrine dysregulation.9,10 Elevated expression of inflammatory mediators, such as adhesion molecules (intercellular cell adhesion molecule-1 [ICAM-1]/vascular cell adhesion molecule-1 [VCAM-1]) and chemokines (e.g., the chemoattractant cytokine ligand [CCL] family), has been detected in ED, highlighting the critical role of shear stress in modulating inflammation via adhesion/chemokine pathways.8,11

Adhesion molecules

Adhesion molecules such as ICAM-1 and platelet endothelial cell adhesion molecule-1 (PECAM-1) expressed on endothelial and immune cells facilitate recruitment of leukocytes and binding of integrins during vascular inflammation. Excessive inflammation can exacerbate ED because of disruption of synthesis of endothelial NO.12,13 Shear stress regulates expression of adhesion molecules in a dynamic fashion. Low shear stress upregulates expression of these molecules to promote inflammation, whereas high shear stress suppresses their expression.14 Shear stress activates the nuclear factor-kappa B (NF-κB) inflammatory pathway through mechanosensors such as Piezo1 and integrins, leading to upregulated expression of ICAM-1/VCAM-1.2,7,15,16,17 These inflammatory factors then promote progression of ED; therefore, there is increasing research interest in developing drugs that target NF-κB.18,19,20 Other signals remain to be explored, including both pro-inflammatory signals (e.g., c-Jun N-terminal kinase) and anti-inflammatory signals (e.g., Krüppel-like factor 2 and nuclear factor erythroid 2-related factor 2 [Nrf2]).10

Chemokines

Chemokines, also known as chemotactic cytokines, are a large family of small secreted proteins divided into four subfamilies, including CC, CXC, CX3C, and XC, with addition of the letter “L” at the end indicating a ligand. CCL functions mainly by binding to CC chemokine receptors, while CXCL binds mainly to the receptor of CXC (CXCR; a class of G protein-coupled receptors) regulating the migration of inflammatory cells in inflammation.21 Chemokines are also regulated by shear stress. Inflammation related to CCL2, CCL7, and CXCL8 can be driven by low shear stress through heat shock protein (HSP)105/70/90 and NF-κB.22,23,24 Nevertheless, their roles warrant further study in ED-associated inflammation.

SHEAR STRESS AND OXIDATIVE STRESS

ED is closely associated with the damage caused by oxidative stress, which is a state characterized by an imbalance between production of reactive oxygen species (ROS) and antioxidant defense mechanisms. There are several primary mechanisms via which oxidative stress contributes to ED. Specifically, superoxides (e.g., nitrite) generated by oxidative stress can damage proteins and reduce the availability of NO. Furthermore, ROS produced by oxidative stress can consume NO and reduce the activity of eNOS. ROS can also damage nitrergic neurons, leading to decreased levels of nitrergic neurotransmitters.25 Systemic inflammation and reduced bioavailability of NO, which promote accumulation of ROS, have been reported to occur when cells are exposed to OSS.26

Oxidative stress regulation by shear stress

Shear stress is important in the regulation of oxidative stress and is discussed in terms of pathological shear stress and physiological shear stress as follows. Generally, pathological shear stress is a risk factor for ED and can induce oxidative stress via a mechanism related to the angiotensin II type 1 receptor/eNOS/NO axis.27 Alleviation of oxidative stress in ED will require the use of drugs that target this pathway, such as tangeretin.28

In contrast, physiological LSS counteracts oxidative stress by activating the Nrf2/heme oxygenase (HO)-1 pathway, which upregulates antioxidant enzymes.29,30,31 Currently, numerous agents, including dimethyl fumarate, salidroside, hesperidin, and fatty acid synthase inhibitors, can leverage the Nrf2/HO-1 pathway to treat ED by restoring redox balance and improving erectile function.32,33,34,35 However, further research is required to delineate whether shear stress directly modulates Nrf2/HO-1 signaling in ED.

Oxidative stress is a common and important pathological phenotype that exacerbates ED. Therefore, there is a need for a greater focus on the role of oxidative stress and antioxidant compounds such as resveratrol and mitoquinone (MitoQ) in ED research in the future.36

Exercise and dual effects of ROS

Exercise can modulate ROS to improve ED under appropriate shear stress derived from exercise. Moderate exercise-induced shear stress could enhance production of NO through ROS-mediated signaling, whereas excessive exercise exacerbates accumulation of ROS, impairing the bioavailability of NO and erectile capacity.37 Clinical evidence supports exercise as an effective intervention to reduce oxidative stress in ED.38

SHEAR STRESS AND CELLULAR BEHAVIOR

Cellular behavior refers to the dynamic activities of cells under physiological and pathological conditions and includes proliferation, differentiation, migration, apoptosis, adhesion, and metabolism.39 A study has demonstrated that shear stress influences cellular behavior through various mechanisms, offering new research directions for understanding ED at the cellular level. Mechanical sensors respond to fluid shear stress, activating intracellular signaling pathways and modulating functions that include proliferation, apoptosis, and migration.40

Cell proliferation

Cell proliferation refers to the process of increasing cell numbers through mitosis or amitosis. Enhancing the proliferation of cells in the corpus cavernosum could repair damaged vascular endothelial and smooth muscle cells, improving erectile function. Changes in shear stress, particularly increased shear stress, are crucial for proliferation of vascular ECs. Therefore, cell proliferation is a way to improve ED via shear stress.41

Changes in shear stress could lead to changes in the proliferative capacity of ECs. The proliferation of vascular ECs (e.g., human dermal microvascular ECs) is boosted when physiological shear stress increases (e.g., to ≥16 dyne cm⁻²).42 However, low shear stress also plays a role in regulating angiogenesis during development of blood vessels by inducing expression of Roundabout 4 (Robo4).43 Furthermore, shear stress may regulate the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) enzyme (a glycolytic regulator) and thereby influence angiogenesis, given that angiogenesis is highly dependent on glycolysis.8 Cell proliferation is also regulated by shear stress through vascular endothelial growth factor (VEGF).44 Shear stress stimulates many substances to promote proliferation of ECs, which is very helpful for repairing vascular endothelium in ED.

Cell differentiation

Cell differentiation refers to the process whereby cells from one or more parent cells develop stable differences in structure and physiological function. Shear stress is an important physical stimulus that can significantly influence the differentiation of mesenchymal stem cells and even immature ECs.45,46

Cells can alter their proliferative state based on the type of shear stress they are exposed to. LSS reduces cell proliferation by arresting cells in G0/G1 phase.47 Turbulent shear stress seems to be a suboptimal condition but could potentially favor differentiation.48 However, low shear stress may cause endothelial–mesenchymal transition, which is a potentially adverse factor in the treatment of ED.7

Cell migration

Cell migration is a highly coordinated process involving reorganization of the cytoskeleton, interactions between cells and the extracellular matrix, and dynamic changes in cell polarity, formation, adhesion, and de-adhesion cycles. Pathological shear stress could reduce adhesion of ECs and trigger compensatory migration to injured sites, thereby repairing disruption of the endothelial barrier.49,50

Cell migration regulated by shear stress mainly depends on the integrin α5β1 sensor. After ECs respond to shear stress signals via the sensor, they first depolarize toward reorientation mediated by Rho kinase, then polarize and migrate via mediation of Ras homolog gene/Rho-associated coiled coil-forming protein kinase (Rho/Rac).51,52 While Rho signaling has been extensively studied in ED, the roles of the Rho/Rac pathways in migration remain underexplored. Of note, growth factors promote directional endothelial migration under shear stress.53 The PFKFB3 enzyme and VEGF are also involved in cell migration, but current ED therapies emphasize the angiogenic role of VEGF, neglecting its potential migratory effects.8,54

Cell apoptosis

Apoptosis is a programmed cell death process that involves activation of gene expression and enzymatic cascades that lead to orderly and biochemical changes.55 Apoptosis of ECs and smooth muscle cells reduces synthesis of NO and impairs vasodilation in ED, collectively contributing to vascular dysfunction. Shear stress-related modulation of apoptosis represents a promising therapeutic target for ED.10

Specifically, LSS could cause apoptosis of ECs, which is associated with downregulation of enhancer of Zester homolog 2 (EZH2) and p21 and upregulation of Caspase 9 and c-Jun N-terminal kinases 2 (JNK2).56,57 Pathological shear stress promotes apoptosis. Peripheral myelin protein 22, programmed cell death 2-like, and Toll-like receptor 2 are involved in apoptosis under OSS.10 Apoptosis of ECs could also be induced by the miR-330/superoxide dismutase 2 (SOD2)/HSP70 signaling pathway under low shear stress.58 These findings offer new insights into therapeutic targets for ED by focusing on shear stress and cell apoptosis. The application of shear stress-induced apoptosis appears to be promising in the treatment of ED.

Stem cell therapy

Stem cell therapy has been shown to be another promising treatment for ED.59 Shear stress could promote stem cell differentiation, proliferation, migration, and other behaviors to improve the efficacy of stem cell therapy.60,61 Moreover, although stem cell therapy does not directly affect shear stress, it alters the vascular mechanical environment. After stem cell therapy, the damaged ECs are repaired, and the pathological vascular structure is reduced.

SHEAR STRESS AND NO

NO is a gaseous signaling molecule that can be synthesized by eNOS and neuronal nitric oxide synthase in the penis.4 It could be mediated by shear stress through mechanosensors in ECs, such as glycocalyx, transient receptor potential vanilloid (TRPV) channels, Piezo1, and PECAM-1.

Glycocalyx

The glycocalyx is the outermost cell membrane layer and consists of proteoglycans and glycoproteins. Proteoglycans contain a core protein (e.g., glypican or syndecan) with multiple glycosaminoglycan chains (such as hyaluronic acid and heparan sulfate). Glycocalyx proteoglycans include hyaluronan proteoglycans, heparan sulfate proteoglycans, and sialic acid proteoglycans.62,63

Studies have shown that LSS can induce release of NO through the mechanosensor glycocalyx, thereby regulating vascular homeostasis.7 Specifically, glypican-1, as a subtype of heparan sulfate, dominates the sensing of shear stress and subsequently activates eNOS via phosphorylation of PECAM-1.64,65,66,67 Furthermore, other research has shown that the expression levels of syndecan-1 and eNOS could be reduced in response to damage to glycocalyx in the penile cavernous vessels, indicating that NO produced by the glycocalyx is involved in erection.68 Although glycocalyx is important as a mechanoreceptor in the production of NO, there is a lack of treatment for the glycocalyx, which needs to be studied further.

TRPV channels

TRPV is a subfamily of the transient receptor potential superfamily that can sense various mechanical forces in ECs.69 Current research indicates that TRPV subtypes 1–4 play an important role in vascular function. TRPV1 and TRPV4 induce production of NO via eNOS under shear stress.70,71 Preclinical studies suggest that ED could be improved by modulating these channels because of the boost in NO levels.72 Currently, there is limited evidence that shear stress affects ED via TRPV1/4, and the roles of TRPV2/3 in ED remain to be studied. However, they show potential in improving ED by influencing NO levels, although the evidence is limited.

Piezo1 channel

Piezo1 is a trimeric mechanosensitive channel and is widely expressed on ECs.15 When Piezo1 is activated by LSS, it triggers a series of downstream events. Briefly, the activated Piezo1 releases ATP, which then activates protein kinase B (AKT) through a specific mechanism. The activated AKT further phosphorylates eNOS, leading to production of NO.73 In contrast, the biological effect of turbulent shear stress shifts to expression of pro-inflammatory genes.74 Notably, the role of Piezo1 in erectile regulation of NO is unconfirmed and warrants further investigation.75

PECAM-1

PECAM-1, also known as CD31, is a surface antigen present on platelets and white blood cells and is also highly expressed at cell junctions in ECs.67 As a mechanical sensor, PECAM-1 contributes to generation of NO and other mechanical responses. LSS promotes the formation of a PECAM-1/VE-cadherin/vascular endothelial growth factor receptor-2 (VEGFR2) mechanical signaling complex at cell junctions, converting mechanical forces into activation of phosphatidylinositol 3-kinase (PI3K) and AKT to stimulate eNOS-derived production of NO.7,67 However, studies indicate that shear stress could also promote formation of the mechanosensory complex by activating the Ras-related protein 1 (RAP1) pathway, thereby activating eNOS.76 Even PECAM-1 can cooperate with glypican-1 to participate in production of NO by sensing shear stress.67 While there are no studies directly relevant to ED, parallels between PECAM-1 signaling and erectile physiology suggest its potential therapeutic relevance.

Other mechanical sensors

In addition to the above-mentioned mechanical sensors, there are the G protein-coupled receptors, as well as neurogenic locus notch homolog protein 1, P2X purinoreceptor 4, primary cilia, caveolae, and others. These mechanical sensors on the vascular endothelium receive relevant signal, which then triggers downstream signaling pathways, leading to biological effects such as inflammation, oxidative stress, cell behavior, and NO. This is the basic mechanism by which shear stress causes ED.

EXERCISE

Exercise is a low-risk and effective non-pharmacological intervention that significantly improves ED by enhancing endothelial function and metabolic homeostasis and reducing inflammation and oxidative stress. It is also a convenient, inexpensive, and broadly applicable way to generate shear stress, increases blood flow, and drives vascular adaptations critical for mitigation of ED. There are also some strategies that could lead to low shear stress, such as prolonged bed rest and vascular surgery.2

Vascular adaptations

Shear stress derived from exercise could regulate vascular structure and function, enhancing vascular adaptability. When applied to cavernous vessels, it could improve erectile function. Shear stress derived from exercise promotes an increase in arterial diameter and structural remodeling77 and may improve vascular relaxation, inflammation, and oxidative stress. These results may reflect an improvement in endothelial dysfunction because of the Krüppel-like factor 2 and miR-181b induced by shear stress.2 In general, appropriate shear stress derived from exercise helps to maintain vascular health and may play a critical role in healthy erectile function.

Effects of exercise duration

Exercise is widely considered to be the secret to health and longevity. This also applies to sexual capacity. A study has found that exercise duration impacts erectile function in various ways.78 Shear stress derived from exercise is consistent with the rule of shear stress affecting NO but varies with exercise duration. Baseline shear stress and NO levels remain stable in untrained individuals. Similarly, acute spikes in shear stress transiently stimulate production of NO to offset hemodynamic stress during moderate exercise.79 However, chronic vascular thickening normalizes shear stress and release of NO in long-term exercisers.79 Exercise is a convenient way to modulate the concentration of NO, which in turn could enhance erectile function. Moreover, moderate exercise increases LSS and alleviates endothelial dysfunction by increasing mitochondrial biogenesis through sirtuin 1 (SIRT1)-related pathways.10 Therefore, exercise-related approaches could be further considered in treatment plans for ED.

DISCUSSION

This review provides a comprehensive perspective on the role of shear stress in ED, elucidating its multifaceted biological mechanisms, ranging from NO and oxidative stress to inflammation and dysregulation of cellular behavior. It redefines ED as a mechanobiological disease rather than merely a vascular or hormonal disorder by highlighting the critical contribution of biomechanical factors to the pathogenesis of ED.

This review explains not only the source of the shear stress but also its effects on ED. Shear stress could come from active exercise, which promotes blood circulation, or from long-term bed rest or vascular surgery, which alters blood flow and vascular structure. The resulting physiological or pathological shear stress signals are received by mechanosensors on the vascular endothelium and are then transmitted as downstream signals to produce various beneficial or harmful physiological effects, thereby improving or worsening ED. The process is summarized in Figure 2.

Figure 2.

The graphic summary of shear stress in erectile dysfunction. TRPV: transient receptor potential vanilloid; GPCR: G protein-coupled receptor; P2X4: P2X purinoreceptor 4; NOTCH1: neurogenic locus notch homolog protein 1; ECs: endothelial cells; eNOS: endothelial nitric oxide synthase; NF-κB: nuclear factor-kappa B; Jnk2: c-Jun N-terminal kinases 2; KLF2: Kruppel like factor 2; Nrf2: nuclear factor erythroid 2-related factor; AT1R: angiotensin II type 1 receptor; NO: nitric oxide; HO-1: heme oxygenase-1; Robo4: Roundabout 4; PFKFB3: 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3; VEGF: vascular endothelial growth factor; EZH2: enhancer of zester homolog 2; SIRT1: sirtuin 1; SOD2: superoxide dismutase 2; HSP70: heat shock protein 70; VEGFR2: vascular endothelial growth factor receptor 2; Rho/Rac: Ras homolog gene/Rho-associated coiled coil-forming protein kinase; miR: microRNA. This picture was created by BioRender (http://www/biorender.com/).

This forward-looking review has some limitations. Although shear stress has been demonstrated in some vascular diseases, most of the evidence for its existence in ED comes from experimental data and some from reasoning and speculation, while clinical data are relatively lacking. These issues mean that there is a need for further experimental research and confirmation. In the future, more clinical studies will be conducted to find novel treatment strategies targeting shear stress in patients with ED.

AUTHOR CONTRIBUTIONS

PHY and TTS provided the conception and design of the study and funding acquisition. PHY and WJD drafted the manuscript. LGC and QJM contributed to the data collection and analysis. PHY, QJM, and TTS reviewed and revised the manuscript. All authors read and approved the final manuscript.

COMPETING INTERESTS

All authors declare no competing interests.