Vascular and musculoskeletal interactions: structure, function, and therapeutic strategies for sarcopenia and osteoporosis

Abstract

Muscle and bone, key tissues that maintain the body’s structure and function, are closely connected via mechanical and biochemical interactions. The vascular system plays a crucial role in musculoskeletal health, not only by providing nutrients and oxygen but also by regulating growth, regeneration, and metabolism. This review systematically examines the vascular structure and function of the musculoskeletal system, and explores the complex biochemical signaling networks involving myokines, osteokines, and vascular-derived factors. Vascular dysfunction is a key contributor to the pathogenesis of degenerative diseases like sarcopenia (SP) and osteoporosis (OP), making vascular-targeted therapies a promising approach for their treatment. Potential strategies for restoring vascular health include molecular targeting, exercise training, nutritional supplementation, cardiovascular pharmacotherapy, hormone therapies, and tissue engineering—all of which may help slow aging-related musculoskeletal degeneration. Despite significant research progress, challenges remain in the clinical translation of these interventions. Future research should focus on elucidating the molecular mechanisms of muscle-bone-vascular interactions and exploring innovative tissue engineering techniques. This review provides a comprehensive understanding of the dynamic interactions between muscle, bone, and vascular systems, highlighting the importance of vascular health in musculoskeletal disease management, and proposes novel vascular-targeted approaches for the prevention and treatment of musculoskeletal disorders.

Keywords

vascular system / musculoskeletal system / sarcopenia / osteoporosis / therapeutic strategies

1 Introduction

Muscles and bones are essential tissues responsible for maintaining the body’s structure and function, developing concurrently early in life to support metabolic and motor demands. This interaction is reflected in the anatomical proximity-generated mechanical effects. Moreover, bone and muscle function as secretory/endocrine organs and participate in complex biochemical communications to coordinate repair and degeneration throughout development and aging [1,2]. Pertinent musculoskeletal degenerative diseases include sarcopenia (SP) and osteoporosis (OP), which are closely related and whose prevalence increases annually with global aging, significantly raising the risks of falls, fractures, and hospitalizations among older patients [1,2].

Muscle and bone are highly vascularized tissues, with blood vessels playing a crucial role in their development, regeneration, and remodeling [3,4]. In addition to supplying oxygen and nutrients and removing metabolic waste products, the vascular system also functions as an active metabolic and secretory organ. Through complex signaling, it interacts with musculoskeletal cells, forming a dynamic biochemical network that significantly influences their physiologic functions [4,5]. According to previous epidemiological research, cardiovascular diseases (CVDs) correlated strongly with musculoskeletal disorders such as SP and OP in older patients. Vascular dysfunction may not only impair tissue regeneration and repair but could also exacerbate the progression of SP and OP, suggesting that vascular health is a key determinant of muscle and bone integrity [6,7].

Despite the increasing recognition of vascular involvement in musculoskeletal health, the intricate interactions between these tissues and their implications for the progression of SP and OP remain underexplored. This review systematically examines the vascular structure and function within the musculoskeletal system, analyzing the complex biochemical and bidirectional signaling networks involving myokines, osteokines, and vascular-derived factors. Furthermore, we explore the role of vascular dysfunction in the pathogenesis of SP and OP and discuss vascular-targeted therapies (Fig. 1). By integrating recent findings, we highlight the importance of maintaining vascular health in the prevention and treatment of musculoskeletal diseases, offering new insights for future research and clinical applications.

2 Vascular structure and physiologic functions of the musculoskeletal system

2.1 Structure and physiologic functions of skeletal muscle blood vessels

The microvascular system of the skeletal muscle originates from one or more arteries, which branche into arterioles and eventually into terminal arterioles. These terminal arterioles are perpendicularly oriented to muscle fibers and supply blood at regular intervals of ~1 mm. Notably, each terminal arteriole supplies 15–20 tortuous capillaries that run parallel to the fibers, creating a dense network around them, which constitutes a microvascular unit, the smallest functional unit of capillary perfusion control [4]. Although arterioles and venules have a similar structure in most mammalian skeletal muscles, aerobic and anaerobic muscles have shown microvascular structure differences. Specifically, aerobic muscles have a higher capillary density, longer capillary length per fiber, and more capillary branches per fiber [8]. Furthermore, the microvessels in these muscles are often embedded deeper into the sarcolemma and have more perivascular mitochondria [9]. These adaptations could enhance the exchange of gases, nutrients, and metabolic wastes.

Intermuscular blood vessels facilitate the transport of gases, nutrients, and metabolic waste around muscle fibers. Blood vessel contraction and distribution influence nutrient transport and exchange of hormones and metabolites between myocytes and plasma [4]. Muscle metabolism is regulated by intramuscular blood flow distribution. As the metabolic rate of skeletal muscle fibers increases, blood flow correspondingly increases to facilitate substrate delivery and metabolite removal [10]. It is also noteworthy that three to five capillaries supply each normal skeletal muscle fiber. During atrophy after sciatic nerve damage, capillaries decrease to 1 per fiber, leading to reduced blood supply, performance decline, and accelerated atrophy [11]. Furthermore, enhanced muscle fiber perfusion may activate satellite cells (SCs), which are crucial for skeletal muscle repair and regeneration [12]. However, the precise molecular signals underlying this process remain incompletely understood. Other benefits of higher vascular density include enhanced oxygen supply and metabolite diffusion, red blood cell (RBC) transit time in capillaries, and muscle cell oxygen uptake, all of which collectively facilitate aerobic metabolism [13]. Therefore, blood flow is a key determinant for muscle fiber growth, metabolic rate, and type conversion [4,12] (Fig. 2).

2.2 Structure and physiologic functions of bone blood vessels

The bone vascular system is complex and highly organized, comprising arteries, capillary networks, and veins [14]. Collectively, these vessels ensure nutrient supply to bone tissue and waste removal [14]. The primary nutrient artery (PNA) is the most crucial artery within the bone. After entering the cortical bone, it splits into ascending and descending branches that extend longitudinally along the diaphysis’ center, which further supply blood to the surrounding areas, including the medulla and the inner two-thirds of the cortex [14]. The PNA branches eventually form a network of sinusoidal vessels, which exit the bone through the principal nutrient vein (PNV), among other venous systems [15]. On the other hand, epiphyseal and metaphyseal arteries enter through both ends of the bone, forming independent capillary networks, which supply blood to the epiphysis and metaphysis [14]. Finally, periosteal arteries and Haversian arteries, connected through Volkmann’s canals, run along the outer bone surface and within the cortical bone, respectively, supplying blood to the Haversian system [14]. Notably, in addition to delivering oxygen, nutrients, growth factors, and hormones, the entire vascular system also maintains bone tissue health and function via ionic exchange and waste removal [15].

Significant proliferation was observed in the actively growing metaphysis of mouse long bones in a study that involved EdU labeling of vascular endothelial cells (ECs). Furthermore, inhibiting angiogenesis significantly decreased bone formation, leading to bone loss and shortened long bones, implying a strong link between bone formation and angiogenesis in the bone microenvironment [16]. The blood supply after a fracture directly affects the bone repair process and healing rate. According to research, reduced blood flow in elderly mice can impair bone repair, a phenomenon consistent with the notion that decreased bone blood flow in older adults compromises bone healing capacity [17,18]. During bone growth and repair, angiogenesis is a critical process that precedes bone formation, with vascular invasion serving as a prerequisite for bone formation and mineralization [19]. Moreover, new blood vessels ensure the transport of circulating osteoblast precursors and osteoclasts to specific sites [20]. Based on these insights, it is plausible that bone formation is a vascular-dependent process. Angiogenesis and osteogenesis are intricately intertwined and inseparable, forming a complex and subtle spatiotemporal relationship known as “angiogenic-osteogenic coupling” [19] (Fig. 2).

3 Impact of muscle and bone-secreted cytokines on blood vessels

The muscle-bone interaction is bidirectional and mechanical. Specifically, skeletal muscles provide kinetic energy and protection to bones, while also applying mechanical pressure to influence bone strength. Meanwhile, bones serve as attachment sites for skeletal muscles, acting as levers that transfer mechanical forces back to the muscles, thus regulating muscle mass. This bidirectional mechanical stimulation is crucial in the bone-muscle link and plays a central role in voluntary movement [1,2]. Multiple reviews have reported that the bidirectional musculoskeletal regulation involves biochemical crosstalk. Muscles secrete myokines such as myostatin (MSTN), insulin-like growth factor 1 (IGF-1), fibroblast growth factor 2 (FGF-2), irisin, interleukin (IL)-6, IL-7, and IL-15, which act on bones. On the other hand, bones secrete osteokines such as osteocalcin (Ocn), FGF23, sclerostin (SOST), prostaglandin E2 (PGE2), RANKL/Wnt-3a, and transforming growth factor-β (TGF-β), which affect muscles [1,2]. Crucially, this biochemical crosstalk extends to the vascular system. Through the systemic and paracrine release of myokines and osteokines, a growing body of evidence firmly establishes that skeletal muscle and bone are not merely passive recipients of vascular signals but are themselves potent regulators of vascular function. The impact of these musculoskeletal-released cytokines on vascular function is illustrated in Fig. 3, and their specific roles are detailed in Tables 1 and 2.

3.1 Impact of muscle-released cytokines on blood vessels

During exercise, muscles produce irisin and IGF-1, both of which enhance endothelial nitric oxide synthase (eNOS) activity to promote endothelium-dependent vasodilation [22,23]. During ischemic stress, IGF-1 further enhances EC stability and function via the PI3K pathway [24]. Additionally, irisin can regulate glucose and lipid metabolism, or inhibit oxidative and nitrosative stress in ECs, thereby alleviating vascular EC damage and apoptosis [25,26].

In contrast to these protective factors, angiotensin II (Ang II) stimulates oxidative stress (OS) and inflammation, leading to endothelial dysfunction and atherosclerosis [27]. In this regard, FGF21 and Apelin can effectively prevent Ang II-induced vascular dysfunction [28,29]. Specifically, FGF21, as an effective endogenous vascular protector, protects brain microvascular ECs from hypoxia-induced damage via HSP72 [30], while Apelin induces ECs to form larger cell cords and blood vessels, thus increasing vascular permeability and promoting blood flow [31].

MSTN, a negative regulator of muscle mass, can upregulate pro-inflammatory markers, causing vascular smooth muscle cell (VSMC) dysfunction [32]. Inhibiting its expression enhances endothelium-dependent vasodilation and β-adrenergic-mediated vascular response, thus improving vascular function [33]. Furthermore, follistatin (FST) and related MSTN inhibitors secreted by skeletal muscle C2C12 cells, effectively suppress vascular inflammation [34]. Although the exercise-induced myokine β-aminoisobutyric acid (BAIBA) effectively combats OS and vascular inflammation, its mechanism of action remains nuanced. It has been associated with an AMPK-dependent pathway [35]; however, other evidence suggests that its anti-atherosclerotic effects might operate through the PGC-1β-ERRα/PPAR-δ and PPAR-γ pathways without altering AMPK phosphorylation [36].

BDNF, expressed in skeletal muscle SCs and myoblasts, promotes angiogenesis by recruiting ECs with TrkB receptors and mobilizing hematopoietic progenitor cells [37]. It also enhances the patency of small-diameter tissue-engineered vessels via stem cell homing and paracrine signaling [38], with its deficiency linked to EC apoptosis and vascular instability [39]. The effects of interleukins on vasculature vary depending on expression context and health status. For instance, IL-7 upregulates lymphangiogenic factors and VEGF-D, thus promoting EC growth, migration, and lymphangiogenesis [40], while IL-15 promotes EC survival and inhibits apoptosis, helping maintain the vascular structure in inflamed tissues [41]. Although IL-6 has been shown to impair endothelium-dependent vasodilation and increase systemic vascular resistance in pregnant rats [42], its acute release from contracting muscle acts as a vital angiogenic signal that stimulates VEGF production and vascular repair [43], highlighting the functional duality of inflammatory cytokines.

Skeletal muscles highly express, synthesize, and secrete VEGFB, especially in oxidative slow-twitch fibers [44]. VEGFB upregulation promotes fatty acid transport in ECs via the fatty acid transporter protein (FATP) [45], enlarges vessel diameter [46], and inhibits OS- and starvation-induced apoptosis, thus promoting vascular survival [47]. Furthermore, exercise further regulates muscle angiogenesis by altering chemokine expression. For example, CXCL10 downregulation may aid EC survival [48], while CXCL1 correlates positively with VEGF and CD31 mRNA expression in muscles [49], suggesting a potential co-regulatory mechanism in exercise-induced angiogenesis that warrants further functional validation.

3.2 Impact of bone-released cytokines on blood vessels

Chondrocytes (CCs), osteoclasts (OCs), osteoblasts (OBs), and immune cells secrete VEGF, which promotes EC proliferation, survival, migration, invasion, angiogenesis, and increases vascular permeability [50]. Beyond VEGF, OBs express and secrete members of the epidermal growth factor (EGF) superfamily, such as EGF-like proteins 6, 7, and 8 (EGFL6, EGFL7, EGFL8), which similarly regulate EC proliferation and vascularization [51–53].

The coupling of angiogenesis and osteogenesis is particularly evident during fracture repair. Bone morphogenetic proteins (BMPs) secreted by OBs stimulate this process via VEGF-A [54], an effect potentiated in coculture systems of MSCs and ECs with BMP-2 [55]. Notably, OBs also deploy counter-regulatory signals, such as CXCL9, which inhibits angiogenesis by competing with VEGF for receptor binding [56]. In contrast, Ocn, another OBs product, provides endothelial protection in atherosclerosis via the PI3K/Akt/eNOS pathway [57,58].

Bone lineage cells, including CCs and OBs, primarily secrete FGFs and vascular cells express their receptors FGFR1 and FGFR2 [59]. Studies have shown that FGF-2 induces VEGF expression in ECs via an autocrine loop, and its systemic administration promotes bone artery dilation and vascular stabilization by upregulating junctional proteins like ZO-1 and VE-cadherin [60]. Conversely, genetic ablation of FGFR1/2 increases vascular permeability and disrupts pericyte coverage [61], underscoring the critical role of FGF signaling in maintaining vascular integrity in bone.

In the skeletal system, slit guidance ligand 3 (SLIT3) secreted by OBs binds to the ROBO1 receptor on H-type ECs, inducing angiogenesis and promoting bone formation [62]. While some evidence suggests that OCs can secrete SLIT3, and its knockdown perturbs H-type vessel formation and bone mass, the precise cellular origin of SLIT3 remains debated, with some studies contesting OCs as its primary source [63,64]. Pre-OCs secrete platelet-derived growth factor-BB (PDGF-BB), which binds to its β receptor (PDGFRβ), promoting MSC and endothelial progenitor cell (EPC) migration and differentiation, thus facilitating H-type vessel formation and osteogenesis [16]. Furthermore, osteoclast-derived matrix metalloproteinases (MMPs), particularly MMP9, facilitate angiogenesis by modulating OC migration, as evidenced by impaired endochondral vascularization in MMP9/13-deficient mice [65]. Moreover, various types of bone cells secrete IGF-1 [66]. In a coculture system of MSCs and EPCs, IGF-1 promoted EPC proliferation via the PI3K/Akt signaling pathway [67].

The RANKL/RANK/OPG pathway, which is closely related to bone metabolism, is crucially involved in vascular calcification. RANKL promotes arterial calcification through OS, inflammation, and potentially by upregulating BMP-2 in ECs [68,69]. In contrast, OPG acts as a decoy receptor to counteract this effect [69]. Similarly, SOST, an osteocyte-derived bone formation inhibitor, protects against vascular calcification by modulating the Wnt/β-catenin pathway and promotes EC angiogenesis via VEGF and placental growth factor [70,71]. Conversely, FGF-23, secreted by OBs and OCs, promotes vascular calcification by inducing the osteogenic differentiation of VSMCs via the ERK1/2 pathway [72]. Beyond its pro-calcific role, FGF-23 also contributes to endothelial dysfunction by increasing superoxide levels and reducing nitric oxide bioavailability [73].

Osteocytes are a major source of PGE2, releasing it through connexin 43 (Cx43) hemichannels to influence muscle and, notably, to induce VEGF expression in OBs and thereby promote angiogenesis [74–76]. The osteocyte-secreted Wnt3a not only participates in mechanosensing but also directly stimulates EC proliferation, migration, and VEGF synthesis [77,78], while also influencing VSMC phenotype and gap junction communication [79]. Finally, TGF-β, primarily stored in mineralized bone matrix and secreted by OBs, exerts dual effects on vasculature. It can induce angiogenesis and remodeling via hematopoietic cell recruitment and VEGF activation [80], yet in other contexts, it drives vascular dysfunction by promoting calcification and inflammation [81]. The specific contextual signals that dictate these contrasting roles remain a central question for future research.

4 Role of vascular-derived factors in muscle and bone

The vascular system, which comprises ECs, VSMCs, and other components, serves not only as a physical barrier that regulates cell and molecule movement between the circulatory system and tissues, but also function as a dynamic organ capable of extensive communication with adjacent tissues and circulating blood cells [82]. Notably, the signaling between vascular cells and musculoskeletal tissues is bidirectional. Vascular cells, including ECs, can interact with musculoskeletal cells via various humoral factors, growth factors, cytokines, chemokines, reactive metabolites, and polarity-related surface molecules [83], as detailed in Table 3 and illustrated in Fig. 4.

The EC-secreted PDGF stimulates the recruitment and proliferation of OBs and MSCs [84]. This pro-regenerative role is supported by animal studies, where PDGF administration enhanced bone callus density and mechanical strength following osteotomy in rabbits [85]. In muscle, PDGF-BB stimulated myoblast proliferation and inhibited differentiation, potentially facilitating muscle regeneration post-trauma [86].

Although quiescent ECs typically do not express VEGF, its expression is rapidly induced by FGF2 or hypoxia [60,87]. VEGF not only directly regulates OB chemotaxis, proliferation, and differentiation but also supports the osteogenic differentiation of MSCs indirectly via angiogenesis [88,89]. However, the impact of VEGF on osteogenesis is not linear, wherein moderate signaling promotes bone formation, but high levels can paradoxically inhibit it [90], suggesting the existence of a precise optimal signaling window. In muscle, VEGF also stimulates stem cell proliferation and differentiation, and protects myoblasts from apoptosis post-injury [91]. Given that VEGF downregulation is identified as a key mediator of impaired muscle regeneration in aging [92], targeting this pathway represents a logical strategy for restoring muscle repair capacity and function.

Among the BMP family members, BMP2 and BMP4 play key roles in EC-pericyte interactions, with their expression significantly upregulated under mechanical stimulation, inflammatory microenvironments, or hypoxic conditions [93]. While BMP-2 induces bone marrow stromal cell (BMSC) differentiation into OBs, thus stimulating Ocn production and leading to mineralized bone formation, BMP-4 exerts a relatively smaller effect [94]. However, targeted BMP2 deletion in ECs does not necessarily affect fracture healing, implying that ECs may not be the primary source of BMP2 in endochondral fracture healing [95]. In muscle, the picture is equally multifaceted. BMP signaling regulates embryonic and fetal muscle development, and blocking this signaling downregulates muscle progenitor cells and SCs [96]. However, BMP2 inhibits uPA expression via the p38MAPK pathway, reducing myoblast differentiation [97]. Additionally, BMP-4 was found to inhibit the myogenic differentiation of BMSCs in mdx mice [98]. These opposing effects highlight that the functional output of BMP signaling is not intrinsic but is determined by the specific tissue and physiologic milieu.

On the other hand, ECs can secrete BMP antagonists such as matrix Gla protein (MGP), FST, and Noggin via exocytosis. Study reported that EC-derived MGP interacts with BMP2 to inhibit ossification in healthy bone and promotes muscle development by suppressing MSTN [99,100]. At the same time, Noggin promotes the maturation of OBs and CCs by guiding pericyte differentiation [16]. Furthermore, it may enhance the myogenic differentiation of bone marrow-derived mesenchymal stromal cells (BM-MSCs), exerting beneficial effects in the treatment of Duchenne muscular dystrophy (DMD) and degenerative skeletal muscle diseases [101]. During bone repair, FST was found to promote cell recruitment, osteogenesis, and angiogenesis. Although FST greatly enhances MSC migration and OB mineralization, its effect on MSC osteogenic differentiation is not as significant [102]. In muscle, FST acts as an antagonist of MSTN and activin to stimulate SC proliferation, muscle hypertrophy, and regeneration, partly by upregulating key myogenic transcription factors like MyoD and myogenin [103].

The vascular endothelium is also a source of the key osteoclast regulators RANKL and OPG [104]. According to research, deleting endothelial-derived RANKL can reduce the number of OCs around ECs, indicating that RANKL’s role in OC proliferation and differentiation [105]. On the other hand, OPG binds to RANKL and prevents its interaction with the RANK receptor on OC membranes, thus inhibiting OC differentiation [106]. Although some studies have associated endothelial-derived OPG with the EC surface, whether it can still interact with RANKL remains unclear [106]. Beyond its role in bone remodeling, RANKL mediates muscle atrophy and dysfunction by upregulating muscle-specific ubiquitin E3 ligases (MuRF1 and Atrogin1) and the NF-κB pathway. In this regard, RANKL inhibition can reduce muscle inflammation, fibrosis, and damage, thus enhancing muscle strength and function [107–109].

Vascular ECs secrete TGF-β, a multifunctional cytokine involved in the regulation of cell proliferation, differentiation, and apoptosis. Notably, TGF-β secretion is inversely correlated with EC density [110]. In skeletal muscle, TGF-β acts as a potent myogenic differentiation inhibitor, repressing the activity of myogenic transcription factors like MyoD through Smad3 signaling and consequently impairing myotube formation [111]. It also promotes muscle atrophy by increasing reactive oxygen species (ROS) production and NAD(P)H oxidase (NOX) activity, which in turn upregulates MuRF1 and Atrogin-1 [112]. This catabolic role in muscle presents a striking contrast to its functions in bone, where TGF-β regulates OB differentiation and bone matrix formation [113], and serves as a vital chemotactic signal guiding MSCs to bone resorption sites for coordinated remodeling [114]. The divergent, context-dependent outcomes of TGF-β signaling underscore its functional versatility across different musculoskeletal tissues.

MMPs are enzymes secreted by various cells, including ECs, responsible for degrading extracellular matrix (ECM) components and playing a key role in tissue remodeling and angiogenesis [115]. For instance, MMP-9 released from ECs rather than OCs is crucial for cartilage resorption to guide directional bone growth [105]. Inhibiting MMP2 can activate the p38/MAPK signaling pathway and promote BMSC osteogenesis [116]. However, in DMD models, MMP2-deficient mice exhibited impaired muscle fiber regeneration and reduced angiogenesis [117]. Notably, while MMP-9 treatment may improve muscle pathology and function during the early stages of this disease, it may impair muscle growth and reduce strength in later stages [118]. However, the primary cellular source of MMP-9 in this context has not been established. Defining its precise origin is a critical next step to understanding the mechanisms behind its roles over the course of the disease.

Vascular cells, including ECs and VSMCs, also secrete many other cytokines and signaling molecules such as IGF-1, Ang II, monocyte chemoattractant protein 1 (MCP-1), endothelin-1 (ET-1), and macrophage colony-stimulating factor (M-CSF), along with various inflammatory chemokines and pro-inflammatory cytokines. Although these factors play critical roles in the intricate interactions between vascular cells and musculoskeletal tissues, their mechanisms are not detailed further in this review.

5 Role of vascular health in SP and OP

SP and OP are common degenerative diseases in the elderly, with high prevalence rates and serving as mutual risk factors. As an age-related syndrome, SP is characterized by progressive and generalized loss of muscle mass, strength, and/or physiologic function. On the other hand, OP is a systemic metabolic disease characterized by reduced bone density, microstructural deterioration, and increased fragility, all of which increase the risk of fractures [119]. Both diseases are often associated with vascular dysfunction, which not only precedes but also accelerates their progression by impairing tissue perfusion, nutrient delivery, and regenerative capacity. Understanding the molecular mechanisms through which vascular decline contributes to musculoskeletal degeneration is crucial for developing novel therapeutic strategies.

5.1 Vascular dysfunction in SP

The progression of SP is strongly associated with a sequence of age-related vascular alterations. In the early stages, functional impairments such as endothelial dysfunction, characterized by a reduced bioavailability of NO and an imbalance in vasoconstrictive factors, limit endothelium-dependent vasodilation and functional hyperemia during muscle activity [120,121]. This initial hemodynamic deficit is compounded by increased arterial stiffness, which reduces arterial compliance and further diminishes bulk blood supply to skeletal muscle, thereby compromising muscle quality and contributing to exercise intolerance [122].

As the condition advances, structural deterioration at the microcirculatory level becomes evident. Capillary rarefaction, commonly observed in aged muscle, weakens the diffusive capacity for oxygen and nutrients, shifting muscle metabolism toward anaerobic pathways and promoting premature fatigue [123]. More importantly, this progressively compromised microvascular environment disrupts critical signaling networks. Reduced shear stress and impaired angiogenic signaling (e.g., downregulation of VEGF and diminished NO production) hinder SC activation, thereby blunting muscle repair and regeneration [12,124]. Concurrently, the sustained endothelial dysfunction fosters a pro-inflammatory state, with increased production of ROS and inflammatory cytokines, which directly activate pathways of muscle protein breakdown, such as the ubiquitin-proteasome system, driving the progressive loss of muscle mass and strength [125,126].

5.2 Vascular dysfunction in OP

The pathogenesis of OP involves a progressive decline in the bone vasculature. A pivotal early event is the loss of specialized H-type ECs, which uncouples angiogenesis from osteogenesis by disrupting the interaction with osteoprogenitor cells, thereby directly undermining bone formation [127,128].

The molecular basis of this vascular decline involves the coordinated dysregulation of key hypoxic and angiogenic signals. For instance, the suppression of the HIF-1α/VEGF axis inhibits the formation of new blood vessels, leading to inadequate blood supply and bone marrow ischemia, which impairs bone remodeling [129]. Furthermore, under sustained pathological stimuli, such as chronic glucocorticoid use, apoptosis of bone ECs is promoted via mechanisms including the disruption of the Akt/mTOR pathway, leading to a profound loss of the vascular network [130,131]. This progressive vascular rarefaction not only starves bone tissue of its blood supply but also fosters a pro-osteoclastic environment that accelerates bone resorption, culminating in the fragile bone phenotype characteristic of advanced OP.

In summary, vascular dysfunction is a key contributor to the pathogenesis of both SP and OP. Through impaired perfusion, disrupted signaling, and dysregulation of critical molecular pathways, it actively drives the degeneration of muscle and bone. Targeting the vascular system therefore represents a promising strategy for mitigating these age-related diseases.

6 Therapies and interventions

Targeting the vascular system to restore its function represents a promising therapeutic strategy for SP and OP. Potential approaches to improving vascular health include molecular targeting, exercise training, nutritional interventions, cardiovascular pharmacotherapy, hormone therapies, and tissue engineering (Fig. 5). While these therapies have been studied independently, emerging evidence suggests that a multimodal approach may yield synergistic benefits. Therefore, understanding their interactions and limitations is crucial for optimizing treatment efficacy.

6.1 Molecular targeted therapy

Targeting specific molecules to stimulate angiogenesis represents a promising translational avenue for alleviating SP and OP. In DMD models, anti-Flt-1 monoclonal antibodies, such as 21B3, inhibited VEGF-Flt-1 binding, enhancing VEGF-mediated angiogenesis, which, in turn, improved muscle vascularization and function [132]. Similarly, intramuscular E-selectin/AAV gene therapy can enhance blood perfusion in ischemic skeletal muscle, promote myofiber regeneration, and improve exercise function [133]. The emerging CRISPR-Cas9 gene-editing technology offers a more precise therapeutic strategy. For instance, targeted co-activation of osteogenic (TGF-β1) and angiogenic (VEGF-A) genes in OBs has demonstrated enhanced bone formation, highlighting the potential of gene editing for simultaneously promoting vascularization and osteogenesis [134]. The clinical translation of these genetic approaches hinges on the concurrent development of safe and efficient delivery platforms, such as nanoparticle-mediated systems, which enable efficient gene editing in ECs of diverse vascular beds, including skeletal muscle microvessels, thereby paving the way for correcting vascular defects in musculoskeletal diseases [135].

Pharmacological promotion of specialized H-type vessels represents another active strategy. Compounds such as SHP-2 inhibitor NSC87877, cathepsin K inhibitor L-235, and harmine can induce PDGF-BB secretion, thus promoting H-type vessel formation and alleviating bone loss [128,131,136,137]. Furthermore, targeting regulators like zinc-finger e-box binding homeobox 1 (ZEB1) with liposomal systems or supplementing with agents like deferoxamine mesylate (DFM) and tetramethylpyrazine has shown efficacy in increasing H-type vessels and bone mass in osteoporotic mice [127,138,139]. Additionally, non-coding RNAs such as miR-497-195 can induce H-type vessel formation by enhancing endothelial Notch and HIF-1α activity, ultimately inhibiting bone loss [140]. While these findings across gene therapy, small molecules, and ncRNAs collectively highlight a diverse toolkit for regulating angiogenesis, their progression to clinical application will require rigorous evaluation of delivery efficiency, target specificity, and long-term safety profiles.

6.2 Exercise training

Exercise plays a vital role in maintaining bone and muscle health. Disuse, such as that resulting from prolonged bed rest or microgravity exposure, significantly increases the risk of SP and OP by reducing mechanical load [141]. Conversely, physical activities like soccer and swimming are associated with enhanced bone density and muscle mass [142–144], benefits that are likely mediated, at least in part, by exercise-induced vascular adaptations.

Compared to the resting state, muscle blood flow can increase up to 100 times during exercise, resulting in adaptive changes in the structure and number of arteries, arterioles, and capillaries, such as increased arterial diameter and reduced wall thickness, which decrease flow resistance and enhance compliance [145]. A comprehensive systematic review of human studies demonstrates that various exercise modalities, including endurance and high-intensity interval training, effectively increase skeletal muscle capillarization [146]. For elderly patients unable to perform regular aerobic exercise, daily stretching has also been shown to improve blood flow, endothelial function, and capillary connectivity in skeletal muscles [147]. These adaptations are largely driven by exercise-induced increases in NO production and vascular shear stress, which stimulate vasodilation and angiogenesis to meet metabolic demands [148]. It is important to note that the transient, low-grade inflammatory response immediately following acute exercise is not detrimental but serves as a crucial initiating signal for this adaptive angiogenesis, helping to recruit immune cells and upregulate pro-angiogenic factors like VEGF [43,149].

Exercise also stimulates bone angiogenesis. Research in rodent models has shown that treadmill running can increase bone marrow blood flow and vascularity, which precedes and accompanies improvements in bone mass [150,151]. The underlying mechanisms are likely related to exercise-induced increases in bone blood flow, interstitial fluid flow, and hemodynamic shear stress, which collectively activate ECs and stimulate osteogenic activity [152–154]. Importantly, the timing of mechanical loading is critical. Studies in rats indicate that delayed loading stimulates vascular remodeling and bone formation, whereas early loading can inhibit these processes [155]. This suggests that the relationship between the vascular network and bone regeneration in response to mechanical loading varies over time. Collectively, although direct evidence from clinical trials remains limited, the preclinical evidence indicates that optimizing exercise regimens to promote bone angiogenesis represents a viable strategy.

6.3 Nutritional supplementation

Adequate nutrition is fundamental to the integrated health of the musculoskeletal and vascular systems. While cardiovascular dysfunction can compromise nutrient delivery, specific dietary components directly influence vascular function, thereby impacting muscle and bone homeostasis.

A balanced diet rich in calcium, protein, essential amino acids, and vitamin D has been considered to support both bone and muscle formation [156]. Beyond baseline needs, specific nutritional strategies show vascular-targeted potential. For instance, a moderate protein intake appears more efficacious than high-protein diets in improving endothelial function and vasodilation [157]. Furthermore, vitamin D may enhance vascular function by facilitating endothelial-mediated vasodilation, promoting anticoagulation, and exerting anti-inflammatory effects. However, clinical evidence supporting these effects remains inconsistent, requiring further validation [158]. Other nutrients, including omega-3 fatty acids, antioxidant vitamins (like vitamins E and C), folic acid, and L-arginine, have been associated with improved endothelial function in both high-risk and healthy populations [159].

Thus, while nutritional interventions represent an accessible strategy for supporting musculoskeletal health through vascular mechanisms, their optimization requires a nuanced understanding of dose-response relationships and individual patient factors.

6.4 Cardiovascular pharmacotherapy

Cardiovascular medications exert diverse and often complex effects on musculoskeletal health. Early research indicated that angiotensin-converting enzyme inhibitors (ACEIs) could delay the decline in muscle mass. However, recent studies have not obtained similar effects on muscle mass and strength [160]. This clinical ambiguity is mirrored by contrasting preclinical findings: ACEIs demonstrated detrimental effects on bone architecture in one mouse study [161], yet protected against OP by blocking the renin-angiotensin system (RAS) in hypertensive rat models [162]. Similarly, angiotensin receptor blockers (ARBs) improve muscle strength in dialysis patients [163] but show no such benefit in murine models [164]. Research has also shown that ARBs may increase bone mass, likely by decreasing bone resorption and promoting CC hypertrophy [165].

Statins not only reduce lipids and slow atherosclerosis progression but also suppress muscle loss [166]. However, their effectiveness in heart failure patients with SP remains controversial. Some studies have demonstrated that statin use reduces leg strength and increases fall risk [167]. Despite the conflicting evidence in OP patients, multiple studies have suggested that statin use increases bone density and reduces fracture risk [168]. The conflicting results may be due to differences in administration routes, statin types, and dosages.

Other drug classes show more unidirectional effects. Phosphodiesterase 5 (PDE5) inhibitors, such as tadalafil and sildenafil, enhance vasodilation and increase blood flow via cGMP to protect muscle fibers in DMD models [169,170]. In OP mouse models, these drugs were found to promote bone formation by upregulating VEGF expression and its receptors [171]. Loop diuretics, in contrast, are associated with an elevated risk of SP in non-dialysis chronic kidney disease patients [172], whereas spironolactone appears to protect against muscle cell apoptosis and contractile dysfunction in heart failure [173]. Moreover, a previous review proposed that some cardiovascular drugs, such as nitrates and beta-blockers, may support bone health, whereas loop diuretics and warfarin are generally detrimental [174].

Collectively, these findings underscore that the musculoskeletal effects of cardiovascular drugs are not class-wide but are critically dependent on the specific agent, patient population, and pathological context. This necessitates a deliberate and evidence-based approach to medication selection in patients with or at risk for musculoskeletal decline.

6.5 Hormone therapy

Systemic hormones are pivotal regulators of musculoskeletal and vascular health, and their decline is a key driver of age-related degeneration [175]. In clinical practice, the combined administration of GH and IGF-1 has been shown to increase skeletal muscle mass and preserve bone density, though its effect on muscle strength is limited. Notably, GH also appears to improve vascular function by enhancing vasodilation [176]. IGF-1, through its receptor (IGF-1R), promotes VSMC proliferation and migration, and its age-related reduction is implicated in cardiovascular complications [177].

Among sex hormones, androgens and estrogens are fundamental. Clinical observations consistently show that testosterone levels are positively correlated with bone density and muscle strength in men [178]. The relationship between testosterone and vascular health, however, is not straightforward. While low levels promote atherosclerosis, the hormone can also paradoxically promote vascular calcification, as evidenced by reduced calcium buildup following receptor deletion in mouse models [179]. This body of evidence implies that maintaining a physiologic range is crucial for vascular protection. Similarly, estrogen protects muscle function by stabilizing muscle fibers and preventing SC apoptosis. In bone, it promotes the osteogenic differentiation of BMSCs, maintaining formation-resorption balance [180]. Its cardiovascular benefits are mediated through enhanced generation of vasodilatory factors like NO, as well as plaque-stabilizing effects via lipid modulation, antioxidant activity, and inflammation reduction [181]. Therefore, the therapeutic application of hormones requires a nuanced approach that carefully considers the distinct, and sometimes contrasting, effects on muscle, bone, and the vasculature, with a focus on dose and timing to maximize benefits and mitigate risks.

6.6 Tissue engineering

Musculoskeletal tissue engineering increasingly prioritizes angiogenesis, employing sophisticated factor delivery and cell-based strategies to build functional vascular networks. Earlier studies showed that VEGF-infused bone scaffolds enhanced neovascularization and endochondral ossification in rat cranial defect models [182]. The field has since progressed to complex co-delivery systems, such as hydrogels releasing VEGF, PDGF, and BMP-2, which have shown efficacy in promoting vascular network formation and regeneration in composite bone-muscle injuries [183]. In muscle regeneration, injectable hydrogels carrying VEGF and IGF-1 can simultaneously drive angiogenesis and muscle regeneration, while also activating SCs and modulating inflammation [184]. Beyond matrices, direct VEGF delivery via engineered myoblasts, systemic injection, or AAV vectors robustly promotes capillary growth in both ischemic and healthy muscle, improving histology and function [185].

Another essential strategy is the application of cell-based therapies, which aim to directly replenish or stimulate the resident cells responsible for vascular and tissue regeneration. EPCs contribute to bone repair by both incorporating into new vessels and recruiting host progenitors via paracrine signals [186]. Similarly, mesenchymal stromal cells (MSCs) are widely investigated for their potent paracrine activity. A recent study demonstrated their ability to significantly promote vessel network maturation and myotube differentiation in engineered 3D muscle constructs, underscoring their therapeutic potential [187]. Furthermore, coculture systems that combine myoblasts, fibroblasts, and ECs on biodegradable scaffolds have successfully generated perfusable vascular networks that enhance graft survival and integration [188]. The advent of induced pluripotent stem cell (iPSC)-derived vascular cells marks a significant advance, yielding self-organizing, perfusable vascular networks that rapidly connect to the host circulation, significantly improving the integration and survival of engineered tissues [189].

Innovative biomaterial design provides the structural and biochemical foundation for these cellular activities. For instance, a porous composite scaffold of bioactive glass and PLGA promotes H-type vessel formation and bone regeneration through a sustained release of bioactive lipids and therapeutic ions [190]. A calcium-phosphate coated magnesium alloy scaffold (Ca-P-Mg) similarly enhances H-type ECs and osteogenesis in large bone defect models [191]. In muscle, a multifunctional silicate ion-releasing hydrogel (SRH) has been shown to promote vascular and muscle fiber regeneration while concurrently inhibiting fibrosis by tuning the material’s properties [192]. Bioactive glass with tailored degradation rates can even stimulate angiogenesis and activate SCs without exogenous factors, enhancing muscle regeneration [193].

While the collective potential of these vascular-targeted engineering strategies is undeniable, their clinical translation hinges on overcoming persistent challenges related to long-term graft stability, controlled immune responses, and the scalability of manufacturing processes for large human tissues.

7 Conclusions, limitations, and future perspectives

The muscle, bone, and vascular systems constitute an integrated microenvironment, dynamically maintained by a web of bidirectional signals. The integrity of this cross-tissue network is increasingly recognized as a key determinant in the progression of aging-related diseases such as SP and OP. Given the vascular system’s central role in this network, its dysfunction would impair tissue repair, disrupt oxygen and nutrient supply, and accelerates musculoskeletal degeneration, contributing to disease severity. Understanding the role of the vascular system in SP and OP pathogenesis could provide valuable insights for developing novel therapeutic strategies.

Despite advancements in understanding vascular contributions to SP and OP, there are several gaps. Much of the current research is based on animal models, which may not fully capture human physiologic complexity. Furthermore, the molecular mechanisms of bidirectional signaling between muscle, bone, and vasculature remain unclear. The heterogeneity of the vascular system, coupled with its diverse responses to physiologic and pathological stimuli, adds significant complexity that necessitates further investigation. Additionally, effectively translating fundamental research into clinical applications remains a substantial challenge.

Future research should prioritize several key directions to bridge these gaps. First, a deeper mechanistic understanding is needed. Employing single-cell and spatial transcriptomics on human tissue samples will be crucial to map the cellular heterogeneity and signaling networks within the muscle-bone-vascular unit in both health and disease. Second, advanced imaging technologies hold great promise. Developing and applying high-resolution imaging techniques, such as photoacoustic imaging or super-resolution microscopy, to visualize the dynamic changes in the microvascular architecture and blood flow in living musculoskeletal tissues could provide unprecedented insights into disease progression and treatment efficacy. Third, the development of more sophisticated human-relevant models is essential. This includes leveraging human organ-on-a-chip systems or organoids that incorporate muscle, bone, and vascular cells to better mimic the human microenvironment and accelerate drug discovery.

From a translational perspective, future efforts should focus on harnessing emerging technologies. In tissue engineering, the design of smart biomaterials that respond to mechanical or biochemical stimuli to release angiogenic factors in a spatiotemporally controlled manner represents a promising frontier. The application of gene-editing technologies like CRISPR-Cas9 offers the potential not only for correcting monogenic defects but also for modulating key regulatory pathways in vascular cells to enhance their pro-regenerative functions. Furthermore, exploring the roles of emerging signaling mediators, such as non-coding RNAs and exosomes, in the inter-tissue communication could unveil novel therapeutic targets and delivery vehicles for targeted therapy.

Finally, a paradigm shift toward personalized, vascular-targeted medicine is anticipated. Future studies should aim to integrate clinical data with multi-omics profiles to identify vascular biomarkers that can predict the risk and progression of SP and OP, enabling early intervention. Combining vascular-targeting strategies with conventional treatments, such as exercise, nutritional plans, or approved medications, may yield synergistic effects and represents a critical area for clinical investigation.

In conclusion, the vascular system is a dynamic and indispensable player in musculoskeletal health. By addressing the existing research gaps through focused mechanistic studies, technological innovation, and robust clinical translation, we can accelerate the development of effective vascular-centric strategies to treat SP and OP, thereby improving the quality of life for the aging population.

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