Advances in vascular endothelial cell-mediated regulation of satellite cell repair and regeneration

Abstract

With advancing age, vascular endothelial cells (ECs) exhibit functional decline and reduced angiogenic capacity, adversely affecting muscle homeostasis. Satellite cells (SCs), serving as the primary stem cells in adult skeletal muscle, are responsible for proliferating, differentiating, and repairing damaged tissue post-injury. Notably, ECs regulate skeletal muscle regeneration not only through angiogenesis-mediated oxygen and nutrient supply to injured areas but also via molecular signaling pathways that modulate SC activation, proliferation, and differentiation. Investigating the regulatory mechanisms of ECs on SCs is crucial for understanding muscle regeneration, repair, and therapeutic strategies for related disorders. This review focuses on EC-mediated regulation of SCs during skeletal muscle regeneration, aiming to elucidate their intricate interplay and provide novel perspectives and theoretical frameworks for advancing research in muscle regeneration and muscle-related disease treatment.

Introduction

SCs are a unique population of adult stem cells residing in skeletal muscle, predominantly maintained in a quiescent state under homeostatic conditions. In steady-state environments, SCs primarily undergo asymmetric division to repair damaged myofibers and sustain the stability of the stem cell pool, with only a subset of SCs retaining proliferative capacity. Upon skeletal muscle injury, activated SCs transition to symmetric division, proliferating and differentiating into myogenic precursors that fuse to form multinucleated myofibers, thereby restoring skeletal muscle integrity and driving regeneration. This tightly regulated process ensures both the replenishment of functional muscle tissue and the preservation of the SC population for future regenerative demands. The interplay between quiescent and activated SC states highlights their dual role in maintaining muscle homeostasis and orchestrating robust repair mechanisms following trauma [1]. ECs—functionally specialized vascular cells forming a contiguous monolayer along capillaries—maintain intimate spatial and functional interactions with SCs within the skeletal muscle's perivascular niche. SCs reside in a quiescent state beneath the myofiber basal lamina, spatially positioned in direct adjacency to capillary ECs. Following muscle injury, EC-SC reciprocal crosstalk coordinates myofiber regeneration coupled with neoangiogenesis, ultimately reconstituting the contractile apparatus and vascular network [2, 3]. The processes of SCs quiescence, activation, proliferation, and differentiation are closely linked to ECs activity, reflecting the intimate association between myofiber regeneration and capillary networks. ECs critically regulate the anatomical positioning and niche dynamics of SCs. Furthermore, ECs modulate SCs behavior through molecular signals, including growth factors, Notch signaling, angiopoietins (Ang), stromal cell-derived factor-1 (SDF-1), Semaphorin 3 A (Sema3A), and other mediators. Understanding EC-mediated regulation of SCs will advance our comprehension of skeletal muscle regeneration and provide a theoretical foundation for developing EC-targeted therapies to repair damaged or aged skeletal muscle.

Anatomical relationship

SCs are anatomically located within the narrow space between the basal lamina and sarcolemma of myofibers, adjacent to the capillary network [4]. A complex array of diffusible signaling molecules—including Wnt, IGF, and FGF—orchestrates bidirectional molecular crosstalk between SCs and myofibers, dynamically regulating their quiescence-to-activation transition. Ultrastructural analysis demonstrates that the average distance between SCs (n = 100) and capillaries is 2.6 ± 3.3 μm, with 82% of SCs positioned < 5 μm from ECs. Approximately 70% of SCs are directly juxtaposed to ECs, forming a "vascular-satellite cell unit". Electron microscopy confirms that SCs and ECs are separated by their respective basal laminae. Two distinct spatial interaction patterns between SCs and ECs have been identified. Direct membrane apposition between ECs and SCs, where their cellular bodies establish close physical contact; Cytoplasmic extensions from distantly located SCs forming transient connections with ECs  [2]. Activated SCs are closer to capillaries than their quiescent counterparts, suggesting that SC proximity to circulating factors is important in their mobilization. Subsequent studies have revealed that the proximity of SCs to ECs regulates SC quiescence. Previous evidence demonstrates an increased spatial separation between type II myofiber-associated SCs and capillaries in aged individuals compared to younger counterparts, which may contribute to the diminished skeletal muscle regeneration and repair capacity observed in aging populations [5, 6]. It is therefore proposed that the spatial proximity between SCs and ECs establishes a structural foundation for both direct cellular contact and paracrine signaling mechanisms.

Satellite cell niche

The niche is a local anatomic milieu instructing SCs to participate in tissue formation, maintenance, and repair. Similar to adult stem cells, SCs are also present in a highly specified niche, which consists of the extracellular matrix (ECM), vascular and neural networks, different types of surrounding cells (e.g., ECs, fibro‐adipogenic progenitor cells (FAPs), fibroblasts, pericytes and immune cells), and various diffusible molecules. The ECM molecules are mainly synthesized and excreted by interstitial fibroblasts but can also be produced and remodeled by myoblasts during muscle development and regeneration [7, 8]. Quiescent SCs reside in an asymmetric niche between the basal lamina and myofiber membrane. To repair muscle, SCs activate, proliferate, and differentiate, fusing to repair myofibers or reacquiring quiescence to replenish the SC niche [9]. The anatomical juxtacapillary positioning of SCs establishes ECs as an indispensable structural and functional element of the SC niche microenvironment. Post-activation, SCs undergo activation, proliferation, and clonal expansion within perivascular compartments—a process exhibiting spatiotemporal coupling with heightened vascular density that parallels SC population dynamics [2]. The functional states of the SC niche include: Quiescent state; Self-renewal state; Proliferative state; Differentiated state; Fusion-competent state  [10]. Skeletal muscle regeneration relies on temporally coordinated regulation of SCs niche dynamics by stage-specific genes. Quiescent SCs are predominantly governed by the nuclear transcription factor paired box gene 7 (Pax7), a SC-specific molecular marker. Upon activation by trauma or stimulation, SCs transition into proliferative and differentiated states, a process orchestrated by the myogenic regulatory factors (MRFs) family, including myogenic factor 5 (Myf5), myoblast determination protein (MyoD), myogenin (MyoG), and myogenic regulatory factor 4 (Mrf4)  [11]. Myf5 and MyoD are predominantly expressed in proliferative undifferentiated cells, whereas MyoG is upregulated during myocyte differentiation, and Mrf4 is associated with late-stage myotube fusion and myofiber maturation. The molecular mechanisms governing SCs niche dynamics involve crosstalk among Notch, Wnt, FGF signaling, and ECM remodeling [12–14]. However, the precise regulatory hierarchy and spatiotemporal coordination of these pathways remain incompletely resolved, particularly regarding the functional interplay between ECs and SCs across distinct niche microenvironments. While current studies suggest Notch receptors function in SCs, conclusive evidence that EC-expressed Notch ligands are indispensable for niche formation is lacking [5]. The molecular mechanisms underlying EC-mediated regulation of distinct SC niche compartments require further investigation (Fig. 1, Table 1).

Fig. 1.

The niche of SCs comprises the ECM, vasculature and neural network, ECs, FAPs, pericytes, and diverse immune cells. Upon muscle injury, immune cells are recruited to the injury site. Created with biogdp.com

Table 1.

The pathways by which ECs regulate SCs

The pathways by which ECs regulate SCs	Role	Ref
Anatomical Relationship	SCs are adjacent to the capillary network formed by ECs, facilitating their mobilization	[2, 4–6]
Satellite Cell Niche	ECs provide the niche for SCs and regulate niche dynamics	[2, 5, 7–9], [10–14]
Growth Factors	VEGF recruits ECs to establish the SC niche, regulates SC quiescence and apoptosis, and modulates myofiber size ECs specifically enhance SC growth through IGF-1, HGF, bFGF, PDGF-BB, IL-6, and IL-10	[15–19], [20–24], [2, 25–28], [29–31]
Notch	ECs-derived Dll4 induces SC self-renewal by activating Notch signaling and enhances reserve cell formation in SCs	[5, 7, 28, 32, 33], [34–38] [39]
Ang	The Ang-1/Tie-2 signaling pathway stabilizes blood vessels, thereby influencing SCs, and regulates the self-renewal of MPCs Ang-2 promotes angiogenesis by interacting with Ang-1/VEGF/Tie receptors, thereby modulating SCs	[40–44] [45–49], [50–54], [55, 56]
SDF-1	SDF-1 induces migration of SC-derived myoblasts, thereby promoting skeletal muscle regeneration	[57–61], [62, 63]
Sema3A	Sema3A regulates EC density to maintain SC niche homeostasis and induces vascular permeability to modulate the SC microenvironment	[64–66]
Other Molecules	Hypoxia activates the Notch signaling pathway to regulate the self-renewal of MPCs. Fatty acids serve as substrates for FAO and participate in FAO-mediated regulation of SC proliferation and differentiation Apln, Postn, and Osm govern myogenesis-angiogenesis coupling. Col IV and laminin comprise the ECM, forming a niche for SCs. Spermidine activates SCs by driving muscle regeneration via the eIF5A pathway and promotes angiogenesis	[10, 67–70] [71–75]

Molecular signaling network

VEGF

The co-regulation of angiogenesis and myogenesis converges on vascular endothelial growth factor (VEGF)—a multifunctional cytokine requiring tight spatial coupling between ECs and SCs within their shared niche microenvironment  [15]. During the differentiation of myogenic progenitor cells (MPCs), VEGF is produced by multiple cell types, including skeletal muscle cells, ECs, and neuronal cells, highlighting its pleiotropic role in coordinating tissue regeneration  [16]. VEGF-mediated angiogenesis occurs through coordinated EC migration, proliferative expansion, lumenogenesis, vascular arborization, and arteriovenous specification—processes that collectively establish angiocrine support for SC functional modulation [17].The fundamental processes of VEGF-driven angiogenesis encompass EC migration, proliferation, lumen formation, vascular branching, and arteriovenous specification [17]. The direct effects of VEGF on myofibers include: VEGF promotes the growth of myogenic fibers and protects SCs from apoptosis. The in vivo activity of VEGF in myofiber regeneration is mediated by VEGFR-2. Current evidence indicates that at least two signaling pathways critical for muscle survival and regeneration are initiated via VEGFR-2 activation in ECs—specifically, the PI3K/Akt and MAP kinase pathways. Activation of Akt signaling in myocytes is essential for suppressing apoptosis during differentiation [18, 19] and regulating myofiber size [20, 21]. In ECs, Akt signaling activation through VEGF-induced VEGFR-2 phosphorylation is critical for ECs survival [22]. VEGF also directly modulates Notch signaling by upregulating both Notch1 and Dll4 in ECs. This signaling cascade is mediated by VEGFR-1 and VEGFR-2 and dependent on the PI3K/Akt pathway [17]. In SCs, the absence of VEGFA leads to reduced Notch activity, which may result from diminished interactions with Dll4 – a ligand highly expressed in ECs [5]. SCs exhibit high expression of VEGFA, which mediates microvascular patterning in skeletal muscle. SCs further recruit capillary ECs via VEGFA to establish a vascular niche, modulating the spatial proximity between blood vessels and SCs to maintain SCs quiescence [5]. SC-derived VEGFA regulates SCs apoptosis through the VEGFA-FLT1-AKT1 signaling axis [23]. Additionally, ECs produce low levels of VEGFA via autocrine secretion to support ECs homeostasis [24].

Furthermore, ECs enhance SCs growth through specific mediators including insulin-like growth factor-1 (IGF-1), hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor-BB (PDGF-BB), interleukin-6 (IL-6), and interleukin-10 (IL-10), thereby modulating muscle regeneration [2, 25]. IGF-1 enhances the proliferative capacity of SCs by activating the PI3K/Akt pathway, which downregulates the cyclin-dependent kinase inhibitor p27^Kip1 and modulates the cell cycle of SCs  [26]. HGF promotes mitogenesis and morphogenesis in ECs through regulation of the HGF/c-Met axis [27] while also activating and stimulating SC proliferation  [28]. During aging, the secretory function of ECs declines, leading to reduced HGF levels. Concurrently, elevated pro-inflammatory factors such as TNF-α further suppress the self-renewal capacity of SCs [29]. bFGF enhances SC proliferation by activating cell cycle-promoting genes Cyclin D1 and c-Myc while suppressing MyoD. It stimulates SC stemness through upregulation of myogenic stem cell markers Pax3 and Pax7, and maintains lineage specification by inducing Myf5 expression to regulate MyoD [30].PDGF-BB promotes myoblast proliferation via enhancement of Akt phosphorylation (Fig. 2) [31].

Fig. 2.

VEGF drives angiogenesis by regulating endothelial cell proliferation, tubulogenesis, and vascular branching, thereby modulating satelite cells. Endothelial cells further promote satellite cell growth through specific factors-including IGF-1, HGF, bFGF, PDGF-BB, IL-6, and IL-10-enhancing muscle regeneration. Created with biogdp.com

Notch

SCs depend on Notch signaling activity. Activation of Notch signaling stimulates the proliferation of SCs and their progeny and thus leads to the expansion of proliferating myoblasts [7]. Notch signaling is associated with the maintenance of quiescence in SCs during development and aging, a hallmark of the undifferentiated stem cell state characterized by Pax7 + SCs [32–34]. Additionally, Notch signaling plays a pivotal role in the formation of the SC niche [28, 35]. In mammalian cells, Notch signaling involves transmembrane ligands (Jagged1, Jagged2, Delta-like 1 (Dll1), Delta-like 3 (Dll3), and Delta-like 4 (Dll4)) and receptors (Notch1-4), which are critical for stem cell maintenance in both homeostasis and disease contexts [36]. Three Notch receptors—Notch1, Notch2, and Notch3—are predominantly expressed on SCs. ECs express Notch ligands Dll1, Dll4, and Jag2, with Dll4 exhibiting the strongest expression under homeostatic (non-injured) conditions [5]. EC-derived Dll4 and Jag2 mediate paracrine signaling through cell–cell interactions with Notch3 and Notch2 receptors expressed on SCs. Activated Notch intracellular domains (NICD) bind to RBP-Jκ to form transcriptional activation complexes, thereby upregulating the transcription of Pax7 and canonical Notch target genes (e.g., Hes and Hey family genes). Hes proteins directly suppress MyoD gene transcription, maintaining the quiescent state of SCs. Notch activation upregulates Pax7 to promote SC self-renewal while suppressing MyoD to block myogenic differentiation [37, 38]. Thus, EC-derived Dll4 induces SCs self-renewal by activating Notch signaling as a juxtavascular niche, augmenting reserve cell formation within the SC pool [5]. ECs secrete TGF-β1, and TGF-β1 negatively impacts at myoblasts differentiation by inhibiting expression of two myogenic regulatory factors (MRF), that is, MyoD and myogenin [39]. Future investigations could explore whether ECs regulate SCs quiescence via TGF-β1 (Fig. 3).

Fig. 3.

Activation of Notch signaling leads to the formation of a nuclear transcriptional activation complex between NICD and RBP-Jk. This complex binds to and transactivates the Pax7 gene, as well as classical Notch target genes such as Hes and Hey. The encoded Hes proteins function as transcriptional repressors, directly inhibiting the transcription of the MyoD gene. Consequently, Notch signaling promotes SC self-renewal by upregulating Pax7, a key regulator of SC identity, while simultaneously inhibiting myogenic differentiation by suppressing MyoD expression, an essential myogenic determination factor. Created with biogdp.com

Ang

Angiopoietin-1 (Ang-1) is predominantly expressed in perivascular cells, including pericytes, vascular smooth muscle cells, fibroblasts, and tumor cells [40–42]. Under conditions of moderate hypoxia, Ang-1 expression in pericytes is augmented in response to increasing hypoxia intensity [43]. PDGF-B has been shown to upregulate Ang-1 expression in smooth muscle cells [44]. Ang-1 serves as a pivotal mediator of vascular maturation, with Tie-2 functioning as its cognate transmembrane receptor [45]. Ang-1 orchestrates critical ECs processes—including migration, adhesion, and survival—through Tie-2-dependent signaling pathways. Ligand-receptor binding of Ang-1 to Tie-2 on ECs promotes vascular stabilization, thereby indirectly influencing SCs homeostasis and function [46]. Additionally, Ang-1 overexpression drives vascular remodeling, characterized by enhanced pericyte recruitment and vascular wall stabilization [47]. The Ang1/Tie-2 signaling axis suppresses myogenic progenitor cell (MPC) proliferation and differentiation via the ERK1/2 pathway. This signaling cascade modulates MPC self-renewal by orchestrating the re-entry of a subset of SCs into a quiescent state. Perivascular cell-derived Ang-1 enhances and sustains the quiescent phenotype of Tie2 + SCs, a mechanism critical for maintaining the stem cell pool. In vitro studies demonstrate that Ang-1 promotes the transcription of myogenic regulators in a MyoD-dependent manner, while simultaneously driving differentiation through upregulation of myosin heavy chain (MyHC) expression. In vivo evidence demonstrates that Ang-1 likely exerts its influence on skeletal myogenesis through Ang1/Tie-2 signaling, wherein Tie-2—primarily expressed on ECs—triggers EC-derived paracrine signaling cascades to regulate muscle regeneration [48].

Angiopoietin-2 (Ang-2) interacts synergistically with Ang-1 and VEGF through Tie receptors, driving the potentiation of angiogenic signaling pathways to promote neovascularization, thereby indirectly regulating SC functionality [49, 50]. Furthermore, its pro-angiogenic efficacy surpasses the individual effects of Ang-1 or VEGF alone in stimulating vascular growth [51]. The rapid responsiveness of Ang-2 to stimuli and its functional interactions with ligands such as Ang-1, VEGF, and Tie receptors enable coordinated regulation of vascular sprouting, maturation, and quiescence, underscoring its critical role in maintaining vascular homeostasis. Ang-2 promotes angiogenesis by competitively binding to the Tie-2 receptor, thereby antagonizing Ang-1-mediated vascular stabilization and inducing endothelial destabilization and activation. This disruption of vascular quiescence facilitates sprouting angiogenesis under pathological conditions [52]. Ang-2 is endogenously expressed by ECs. Previous studies have demonstrated the pro-regenerative role of the Ang-2 receptor in skeletal muscle repair [53]. However, emerging evidence highlights its detrimental effects: Ang-2 drives SC hypertrophy and myofibroblast differentiation, thereby contributing to muscle atrophy and fibrosis [54]. NOX2-dependent ROS production serves as an upstream signaling pathway for Ang-2-induced fibrotic remodeling, with TGF-β and its downstream mediator connective tissue growth factor (CTGF) identified as critical regulators in this pathological cascade  [55, 56]. Current studies on the role of Ang-2 in modulating SCs behavior during skeletal muscle regeneration remain controversial, with conflicting evidence regarding its pro-regenerative versus fibrogenic effects. Future investigations should prioritize elucidating the spatiotemporal dynamics of Ang-2 signaling within SC niches, particularly its context-dependent interactions with: Tie-2 receptor clustering and downstream PI3K/Akt/FOXO1 pathways, Integrin-dependent crosstalk, ROS-mediated redox signaling and its interplay with TGF-β/CTGF cascades and VEGF-A synergy in hypoxic microenvironments.

SDF-1

Stromal cell-derived factor-1 (SDF-1), also designated CXCL12, functions as a pivotal chemokine governing cellular migration in tissue homeostasis and repair. Its signaling is mediated by two cognate receptors—CXCR4 and CXCR7—with CXCR4 being the primary high-affinity receptor expressed on SCs [57]. Notably, SDF-1 acts as the endogenous ligand for SCs surface CXCR4, mediating SC homing and activation responses during muscle regeneration. Under hypoxic conditions, ECs upregulate SDF-1 expression via the HIF-1α signaling pathway [58]. Additionally, inflammatory cytokine stimulation activates the NF-κB pathway in ECs, further inducing SDF-1 synthesis [59]. SDF-1 enhances MMP activity and upregulates adhesion proteins such as CD9 by activating focal adhesion kinase (FAK), cell Division control protein 42 (CDC42), and Ras-related C3 botulinum toxin substrate 1 (RAC-1), thereby reorganizing actin cytoskeleton dynamics to induce the migration of SC-derived myoblasts, as well as other stem cells and stromal cells, which collectively promote skeletal muscle regeneration [60–62]. Additionally, SDF-1 downregulates miR-10a, miR-425, and miR-5100 to reduce the expression of Dll1 and Jagged2, thereby modulating Notch signaling transduction [63].

Sema3A

Semaphorin 3 A (Sema3A), a guidance chemorepellent protein, functions as a selective inhibitor of VEGF-mediated angiogenesis. It targets ECs by antagonizing Src and FAK signaling cascades to suppress EC motility and vascular sprouting [64]. In ECs, Sema3A acts as a competitive ligand for neuropilin-1 (NRP-1), effectively antagonizing VEGF-165–mediated mitogenic signaling in ECs by disrupting VEGF/NRP-1 complex formation [65]. This regulatory axis fine-tunes EC population dynamics, potentially contributing to maintenance of the SC niche’s structural and functional integrity through vascular niche stabilization. Sema3A and VEGF further orchestrate vascular permeability through coordinated NRP-1 expression, thereby modulating the biophysical and biochemical properties of the SC niche. Intriguingly, SCs upregulate Sema3A in response to mechanical muscle crush injury, enabling precocious axonal ingrowth into regenerating myotubes via neurorepulsive guidance [66]. HGF, Fibroblast Growth Factor 2 (FGF2), and VEGF function as potent paracrine activators of Sema3A expression in SC-derived myoblasts, operating through ligand-receptor binding to amplify Sema3A transcriptional activity and protein synthesis [65]. ECs likely exert regulatory control over SC niche homeostasis by secreting these angiocrine factors to modulate Sema3A bioavailability, thereby calibrating SC quiescence-activation transitions via neurovascular signaling crosstalk. The precise molecular mechanisms and signaling pathways by which ECs regulate SC dynamics via Sema3A remain incompletely elucidated. Systematic investigation is required to resolve the spatiotemporal coordination of these growth factors in modulating Sema3A transcription, post-translational modifications, and functional bioavailability within the SC niche. Critical knowledge gaps persist regarding crosstalk between Sema3A-mediated axonal guidance signaling and VEGF-dependent angiocrine pathways during neuromuscular regeneration, particularly under pathological conditions marked by EC dysfunction.

Other molecules

ECs can also modulate SCs by regulating oxygen partial pressure and metabolic substrates (e.g., fatty acids) within the local microenvironment. This regulation primarily occurs through NO produced by endothelial nitric oxide synthase (eNOS) in the vascular wall, which governs blood flow and blood pressure, thereby influencing oxygen partial pressure [67]. Research has revealed that hypoxia activates Notch signaling, which subsequently suppresses MyoD to inhibit SCs differentiation, while upregulating Pax7 and promoting self-renewal of MPCs through canonical Hes protein-mediated repression of miR-1/206 [10]. Mitochondrial ATP production, but not total ATP levels, drives endothelial FA uptake and transport via acyl-CoA formation in mitochondrial/ER microdomains [68]. This process supplies substrates for mitochondrial fatty acid oxidation (FAO) in satellite cells, and their activation, proliferation, and Differentiation rely on the mitochondrial FAO pathway. The study reveals that genetic ablation of carnitine palmitoyltransferase 2 (Cpt2, the rate-limiting enzyme for FAO) alters metabolic flux in SCs, leading to energy insufficiency and reduced cellular acetyl-CoA levels. Consequently, protein acetylation—particularly of Pax7—is diminished, thereby altering its transcriptional function and significantly impairing SC differentiation capacity, ultimately delaying muscle regeneration [69].Molecular profiling of ECs and SCs sorted from regenerating muscle allowed the identification of three effectors, Apln, Osm, and Postn, that were shown to stimulate myogenesis/angiogenesis coupling and to be required for muscle regeneration. Experimental evidence from murine models indicates distinct cellular origins for these factors: Apln is predominantly EC-derived, Osm is primarily macrophage-secreted, and Postn shows dominant expression in FAPs [70]. ECs express laminin α4 and α5 chains that combine with laminin β1 and γ1 chains to form laminins 411 and 511 (isotypes 8 and 10) [71]. ECs secrete type IV collagen (Col IV) [72]. Laminin (LN) and Col IV are essential constituents of the extracellular matrix (ECM). The ECM serves as a macromolecular scaffold that provides structural support to cells and establishes a microenvironmental niche for transmitting regulatory signals to SCs [73]. Spermidine, a naturally occurring polyamine ubiquitously present in all human cells, has been demonstrated in murine models to enhance the angiogenic function of ECs [74]. Concurrently, it activates eIF5A in SCs, thereby promoting the translational efficiency of myogenic factors (e.g., MyoD) to directly drive muscle regeneration [75]. Further investigation into EC-mediated regulation of SCs via spermidine is warranted.

Conclusion

Skeletal muscle regeneration is a tightly coordinated process that relies on the synergistic actions of diverse cell populations, including immune cells, FAPs, and vascular ECs. These cells execute their specialized functions to ensure functional muscle recovery while preventing the onset of muscle-related pathologies [70, 76–78]. The key players in skeletal muscle regeneration are ECs and SCs. Muscle healing progressively depends on cytokines or molecular signals secreted by ECs. Since SCs are essential for muscle regeneration, therapeutic strategies targeting SCs have been developed for muscular Disorders. However, human SC transplantation has not achieved the expected outcomes, necessitating novel therapeutic strategies, such as those focusing on intercellular interactions, to advance skeletal muscle regeneration. Additionally, several unresolved issues in muscle regeneration warrant attention: 1) The mechanisms by which ECs regulate SCs, including the molecular signaling pathways involved, remain incompletely characterized;2) How ECs modulate SCs under pathological conditions is poorly understood;3) Targeting endothelial cells represents a promising cell-based therapeutic strategy for muscle-related diseases, warranting further development and application. For instance, upregulating Dll4 on ECs activates SCs proliferation and differentiation through Dll4-Notch signaling, while concurrently promoting angiogenesis to provide metabolic support for regeneration. Previous studies have employed intramyocardial injection of synthetic modified RNA (modRNA) encoding human VEGFA to enhance neovascularization and promote the expansion and directed differentiation of endogenous cardiac progenitor cells in murine myocardial infarction models [79]. Given that SCs represent a type of stem cell, this methodology may be leveraged to upregulate VEGF expression, thereby facilitating muscle neovascularization and modulating SC function. Future studies may also enhance Ang-1/Tie-2 signaling to modulate ECs migration, adhesion, and survival during muscle regeneration, while regulating MPC self-renewal via the ERK1/2 pathway.

Therefore, skeletal muscle regeneration is critically important for patients with chronic diseases as well as healthy aging individuals. Thus, elucidating the crosstalk mechanisms between ECs and SCs during muscle regeneration demands comprehensive investigation.

Authors’ contributions

Chunyan Yang conceived, wrote, and edited the manuscript. The author(s) read and approved the final manuscript.

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The authors declare that they have no competing interests.