Vascular mechanical forces and vascular diseases

Graphical abstract

Highlights

• •Identifies mechanosensors and signaling pathways of vascular mechanical forces.
• •Elucidates how mechanical forces drive vascular disease progression.
• •Uncovers hydrostatic pressure’s underestimated role in atherosclerosis and hypertension.
• •Highlights research gaps and propose future directions for vascular mechanical forces research.

Abstract

Background

Blood vessels are continuously exposed to mechanical forces, mainly including shear stress, cyclic stretch, and hydrostatic pressure. These forces regulate the functions of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) through complex mechanosensing and signal transduction pathways, which are essential for maintaining vascular homeostasis. However, under pathological conditions, they can contribute to the development of vascular diseases, such as atherosclerosis, hypertension, and aortic aneurysm.

Aim of review

This review aims to synthesize the mechanosensors and downstream signaling pathways of vascular mechanical forces in ECs and VSMCs, emphasizing their effects on cell behaviors and their involvement in the onset and progression of atherosclerosis, hypertension and aortic aneurysms.

Key scientific concepts of review

Multiple molecules and structures – including ion channels, G-protein coupled receptors, cellular junction molecules, and other membrane structures – act as mechanosensors of vascular mechanical forces and trigger multiple downstream signal transduction pathways. The pathological alterations in shear stress, cyclic stretch, and hydrostatic pressure regulate the functions and behaviors of ECs and VSMCs, including cellular proliferation, migration, apoptosis, oxidative stress, endothelial permeability, etc. These responses induce vascular inflammation, dysfunction and remodeling, which eventually contributes to the onset and progression of atherosclerosis, hypertension, and aortic aneurysms. This review also highlights the underestimated role of hydrostatic pressure in atherosclerosis and hypertension, as well as other research gaps and future directions for vascular mechanical forces research. Understanding and therapeutically modulating these biomechanical pathways may ultimately facilitate more effective prevention and treatment of vascular diseases.

Introduction

The cardiovascular system is subjected to a variety of mechanical forces integral to maintaining vascular homeostasis and function. Among these forces, shear stress, cyclic stretch, and hydrostatic pressure play pivotal roles in regulating the behavior of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) [1]. However, under pathological conditions, aberrant forces can drive the onset and progression of various vascular diseases, including atherosclerosis, hypertension, and aortic aneurysms. These diseases are among the leading causes of morbidity and mortality globally, underscoring the need for a deeper understanding of their underlying mechanisms.

While the significance of mechanical forces in vascular diseases is widely acknowledged, substantial gaps persist in understanding how these forces are sensed and transduced in ECs and VSMCs, as well as their involvement in various vascular diseases. Herein, this review comprehensively synthesizes current knowledge regarding vascular mechanical forces, centering on their mechanosensing and signal transduction processes, their impacts on vascular cells, and their roles in the pathogenesis of vascular disease.

Overview of vascular mechanical forces

Fluid shear stress is defined as the frictional force per unit area exerted on the vessel wall by the flowing blood as it moves through the vessel. This force primarily acts on the ECs, which are located on the inner surface of the vessels, in the direction of blood flow and parallel to the vessel wall [1]. The magnitude of shear stress (τ) is determined by several factors, including the blood flow velocity (Q), blood viscosity (μ) and the diameter of the blood vessel (R), as described by the Poiseuille’s Law $\tau =\frac{4\mu Q}{{\pi R}^3}$ [2]. Specifically, the range of shear stress in different types of blood vessel is 10∼70 dynes/ cm² for arteries and 1∼6 dynes/cm² for veins. Different blood flow patterns in the vessel system give rise to different types of shear stress. When the blood flow is laminar and steady, typically observed in the straight part of large arteries (e.g., the main part of the thoracic aorta), the shear stress is uniform and in a single direction. This type of shear stress is known as laminar shear stress. In contrast, in curved vessel segments or at vessel bifurcations (e.g., the inner curvature of the aortic arch), the multidirectional and turbulent flow generates low or oscillatory shear stress. It has been well-established that laminar shear stress is anti-inflammatory and protective against atherogenesis, while low or oscillatory shear stress contribute to endothelial inflammation and dysfunction [[3], [4], [5]].

Cyclic stretch refers to the repetitive expansion and contraction of blood vessels in response to the pulsatile blood flow generated by the heart. This stretch and recoil occur during each cardiac cycle, with arteries expanding as blood is pumped into them and contracting as the heart relaxes. Cyclic stretch helps maintain blood flow, regulates vascular tone, and contributes to the remodeling of blood vessels over time [6]. The magnitude of cyclic stretch, which refers to the extent of expansion of vessels, is influenced by several factors such as blood pressure, vascular compliance, and the stiffness of surrounding supportive tissues. Generally, higher blood pressure, greater vascular compliance, and more compliant surrounding tissues result in a larger stretch. Under physiological conditions, the magnitude of cyclic stretch in larger arteries, such as the aorta, typically range from 10 % to 15 %, while smaller arteries normally experience an expansion of 5 % to 10 % during each heartbeat [7]. In most cases, cyclic stretch occurs circumferentially around the vessel wall. Smaller vessels and veins may experience light axial stretch in addition to circumferential stretch. Consequently, ECs and VSMCs in the vessel wall are also subjected to both circumferential and, to a much lesser extent, axial stretch.

In addition to the shear stress parallel to the vessel wall and cyclic stretch predominantly in a circumferential direction, blood flow can also exert a force perpendicular to the vessel wall due to gravity. This force is called hydrostatic pressure. The magnitude of the pressure is influenced by several factors, including blood volume, cardiac output, blood flow velocity, vascular resistance, and the vertical position of the blood column. Hydrostatic pressure affects fluid exchange between capillaries and tissue interstitial spaces, and excessive hydrostatic pressure can lead to tissue edema. Physiological systolic blood pressure in adults typically ranges from 90 to 140 mmHg [8]. Thus, hydrostatic pressure acting on the vessel wall has a much higher order of magnitude compared to shear stress or cyclic stretch. Elevated hydrostatic pressure is also the most direct manifestation of hypertension, suggesting that it may play an important role in hypertension-associated vascular pathophysiological changes. However, studies exploring the potential role of hydrostatic pressure in vascular function are relatively limited compared to those on shear stress and cyclic stretch (Fig. 1).

Fig. 1.

An overview of vascular mechanical forces. Mechanical forces in vessels mainly include shear stress, cyclic stretch, and hydrostatic pressure. Shear stress includes two types: i) laminar and high shear stress under laminar blood flow; ii) low or oscillatory shear stress under disturbed flow condition. Image created with BioRender.com, with permission.

Mechanosensing and signal transduction of vascular mechanical forces

Both ECs and VSMCs can sense these mechanical forces through specialized mechanosensors, which activate downstream intracellular signaling pathways that regulate cellular behavior and maintain vascular homeostasis [7]. Given that mechanical signals do not involve traditional ligand-interaction, it has been challenging to identify mechanosensors responsible for sensing the forces. Nevertheless, a number of mechanosensitive molecules on ECs and VSMCs have been identified, mainly including mechanosensitive ion channels, G-protein coupled receptors (GPCRs), cellular junction molecules and other membrane structures [[9], [10], [11], [12]]. This section highlights mechanosensors and signaling pathways of these force.

Shear stress

One of the earliest discovered mechanosensors of shear stress is platelet endothelial cell adhesion molecular 1 (PECAM-1), a transmembrane glycoprotein belonging to the immunoglobulin superfamily that is highly expressed on ECs, platelets and certain immune cells. It functions as a cell-adhesion molecule, acting cooperatively with different junctional proteins to form adherent junctions between ECs [13,14]. PECAM-1, together with VE-cadherin and vascular endothelial growth factor receptor2 (VEGFR2), forms a mechanosensory complex which activates the downstream PI3K/Akt and ERK under shear stress [[15], [16], [17]]. Both PI3K/Akt and ERK pathway can induce the activation of endothelial nitric oxide synthase (eNOS) and the production of nitric oxide (NO) [18,19]. It was also observed that PECAM-1 directly interacts with eNOS at ECs adherens junction sites, and the PECAM-1/eNOS complex dissociates under shear stress, accompanied by an increase in eNOS activity [20]. In addition to NO release, the PECAM-1/VE-cadherin/VEGFR2 mechanosensory complex also involves in the activation of integrins via PI3K, thus facilitating growth of focal adhesions, the alignment of ECs, and activation of the NF-kB inflammatory pathway [16,21]. The fact that PECAM-1 acts as a primary mechanosensor for shear stress was confirmed through magnetic bead experiment and has been recognized for a long time [15,16]. However, a recent study identified PlexinD1 (PLXND1) as a novel shear stress mechanosensor acting upstream of the PECAM-1 mechanosensory complex [22]. More research is needed to elucidate the interactions between PLXND1 and the mechanosensor complex.

Piezo-1, expressed in both ECs and VSMCs, is a mechanosensitive non-selective cation channel that plays a crucial role in sensing shear stress [23,24]. Upon mechanical activation, Piezo-1 facilitates the influx of cations (primarily Ca²⁺) into cells. The resulting rise in intracellular Ca²⁺ serves as a critical mediator, regulating multiple endothelial functions, such as NO production and vasodilation. For example, Ca²⁺ influx has been shown to induce the release of adenosine triphosphate (ATP) and activation of calpains [25,26]. Wang et al. [27] further demonstrated that Piezo-1-induced ATP release activates the downstream P2Y2/Gq/G11 pathway, leading to phosphorylation of Akt and endothelial nitric oxide synthase (eNOS), and ultimately increasing NO production. Other signaling pathways involved in this process include protein kinase N2 (PKN2) [28] and phosphorylated Ca²⁺/Calmodulin-dependent protein kinase type II (p-CaMKII) [29]. Besides, the disturbance of intracellular calcium homeostasis also contributes to regulating fiber orientation, cell alignment, and adherens junctions in ECs via the upregulation of Ca²⁺-activated protease calpain pathway. Further in vivo studies underscore the essential role of Piezo-1 in vascular development: knockout in mice leads to embryonic lethality within days of the heart beating, while haploinsufficiency causes endothelial abnormalities in developing vessels [24,30]. Another point worth of noted is that cation influx following Piezo-1 activation induces depolarization of ECs, which are structurally and electrically connected to VSMCs. This indicates that Piezo-1 activation may indirectly lead to the depolarization of VSMCs and vascular constriction, as confirmed by research [9,31].

Other mechanosensitive ion channels involved in shear stress signaling transduction include Transient Receptor Potential Vanilloid 4 (TRPV4, a nonselective cation channel that is more permeable toCa²⁺), Kir2.1 (a K⁺ channel), and TREK1 (a K⁺ channel) [[32], [33], [34], [35]]. Studies have demonstrated that these channels also contribute to NO production and alteration in the membrane potential of ECs, ultimately resulting in vasodilation, similar to Piezo-1 [36,37]. Nevertheless, the issue regarding whether these mechanosensitive ion channels act as primary mechanosensors remains a subject of controversy. Some studies suggest that Piezo-1 and GPCRs may function as sensors upstream of these channels [[38], [39], [40], [41]]. Furthermore, epithelial sodium channel (ENaC) has been shown to sense shear stress and play a bidirectional role in regulating vasomotion [[42], [43], [44], [45]]. Under normal conditions, ENaC participates in vasodilation induced by laminar shear stress. However, overexpression or gain-of-function mutations of ENaC can lead to vasoconstriction, potentially due to an increased Na⁺ influx that attenuates arginine uptake by cationic amino acid transporters.

In addition, other mechanosensitive molecules have also been identified. These include GPCRs (e.g., GRP68, Sphingosine-1-phosphate receptor 1), as well as specialized membrane structures (e.g., glycocalyx, caveolae, integrins) [[46], [47], [48], [49]]. It has been demonstrated that these molecules take participation in shear stress-induced cellular responses, like NO release and vasodilation. However, the question of whether these mechanosensitive molecules function as direct receptors or as transducers, and particularly the crosstalk between different signaling pathways, remains insufficiently understood. In summary, the involvement of different mechanosensitive molecules in shear stress sensing and signal transduction is complex and interactive. Different molecules can trigger similar downstream effects, such as NO production and changes in cell membrane potential. Further investigations are essential to clarify the intricate roles of these molecules and their interactions.

Cyclic stretch and hydrostatic pressure

Compared to shear stress, which has been more extensively studied, the understanding of the mechanosensing and signaling pathways of cyclic stretch and hydrostatic pressure remain relatively limited. And there is partial overlap among the identified mechanosensitive molecules of three forces, such as ion channels, integrins, and caveolae. Specifically, for cyclic stretch, ion channels, cellular adhesion proteins, cytoskeleton proteins have been considered as mechanosensitive molecules, which active downstream CaMKK2/AMPK, MAPK, ERK, PI-3 K/Akt, and FAK-cytoskeleton pathways [12,[50], [51], [52], [53], [54]]. For hydrostatic pressure, Piezo-1 has been demonstrated to be its mechanosensor in ECs, which subsequently regulates VE-cadherin adhesion [55,56]. Another potential mechanosensitive ion channel is ENaC, which mediates Ca²⁺-dependent myosin activation in the immediate response of ECs to hydrostatic pressure [57]. In addition, caveolae-dependent mechanisms may also play a role in hydrostatic pressure sensing and signalling [58]. To sum to, the comprehension of the mechanosensors and mechanotransduction mechanisms of cyclic stretch and hydrostatic pressure remain poorly understood and require further investigation (Fig. 2).

Fig. 2.

Mechanosensors involved in vascular mechanical forces transduction. ECs and VSMCs sense vascular mechanical forces via multiple mechanosensitive structures, including ion channels, PECAM-1 complex, GPCRs, caveolae, glycocalyx, and integrins. Key processes in downstream signaling transduction include PI3K/AKT, MAPK/ERK, Ca2 + influx, which then regulate cell responses, NO production, oxidative stress, etc. Image created with BioRender.com, with permission.

Vascular mechanical forces and vascular diseases

Vascular mechanical forces and atherosclerosis

Atherosclerosis (AS) represents a chronic and progressive vascular ailment that is characterized by the accumulation of lipids, diverse cell types, and fibrous tissue within the vessel wall. The initiation of AS is predicated upon endothelial dysfunction and activation, thereby triggering the retention and oxidation of low-density lipoprotein (LDL) within the intima. Then a cascade of pathophysiological events follows: the infiltration of monocytes, the migration and proliferation of VSMCs, and the perpetuation of vascular inflammation. The terminal stage of AS is characterized by either the stabilization or rupture of atherosclerotic plaque. Notably, the involvement of vascular mechanical forces has been demonstrated to be of paramount importance in the pathophysiology of AS, exerting a profound influence on both its onset and progression. This aspect will be discussed in the subsequent section of this review (Table 1).

Table 1.

Representative in vivo and in vitro models for studying vascular mechanotransduction in atherosclerosis.

Pathological process	Mechanical force	Model type	Description	Key findings	Representative reference No.
Athero-prone areas	Low/oscillatory shear stress	In vivo, human	Calculating shear stress in arteries	Regions with low and oscillating shear stress predisposed to AS	[[59], [60], [61]]
	Low/oscillatory shear stress	In vivo, mice	A perivascular shear stress modifier	Low and oscillating shear stress induced larger and vulnerable plaque	[62]
Impaired endothelial barrier	Low/oscillatory shear stress	In vivo, porcine	Inner, outer curvature and the cranial part of thoracic aorta	Disrupted VE-cadherin junction/catenin complex	[70]
	Low/oscillatory shear stress	In vitro, HUVEC	A parallel plate apparatus, 0.5 ± 4 dynes/cm2	Reduced expression of ZO1 and Occludin	[66]
	High cyclic stretch	In vitro, HUVEC	A force-loading device, 15 % elongation	Impaired cell–cell contact	[115]
Endothelial dysfunction	Low/oscillatory shear stress	In vitro, HUAEC	Ibidi pump system chamber, static condition	Reduced eNOS phosphorylation and NO formation	[28]
Oxidative stress	Low/oscillatory shear stress	In vitro, HUVEC	A parallel flow chamber, 3 dynes/cm2	Increased ROS via AT1R/eNOS/NO.	[89]
	High cyclic stretch	In vitro, HAEC	Flexcell FX-4000 T system, 15 % elongation	Increased superoxide anion production and reduced NO bioavailability	[117]
Chronic inflammation	Low/oscillatory shear stress	In vivo, rabbit	Ligation of left common carotid artery	Increase expression of VCAM1 in EC	[91]
	Low/oscillatory shear stress	In vitro, HUVEC	A parallel-plate flow chamber system, 4.14 dynes/cm2	Increased expression of CX3CR1 and VCAM1	[94]
	Low/oscillatory shear stress	In vivo, rat	Ligation of left carotid artery and left renal artery	Increased expression of MCP-1 in EC	[96]
Foam cell formation	Low/oscillatory shear stress	In vitro, EC and SMC	A designed EC–SMC coculture model	Increased SMC migration	[99]
	High hydrostatic pressure	In vivo, Yucatan minipig	Inflatable suprarenal aortic cuffs	Cephalad hypertension accelerated coronary atherosclerosis to almost 5-fold	[109]
	High hydrostatic pressure	In vitro, VSMC	MechanoCulture TR stimulator, 180/120 mmHg	VSMC foam cell formation and lipid droplet accumulation	[110]
Plaque vulnerability	High shear stress	In vivo, human	Calculating shear stress in AS lesion	Rupture-prone region	[105]
	High cyclic stretch	In vitro, VSMC	Flexcell I flexible membrane base, 20 % elongation	Increased expression of PUMA	[120]

AS, atherosclerosis; HUVEC, human umbilical vein endothelial cell; VSMC, vascular smooth muscle cell; HAEC, human aortic endothelial cell.

Shear stress and atherosclerosis

Initiation of atherosclerosis: endothelial dysfunction and lipid accumulation

It has been unequivocally established over an extensive period that atherosclerotic lesions preponderantly manifest at arterial branch points, curvatures, and bifurcations, and do not occur randomly throughout the vascular tree. This phenomenon endures notwithstanding the fact that systemic atherosclerotic risk factors induce endothelial dysfunction across the entire vasculature. In the regions highly prone to atherosclerosis, the blood flow and shear stress characteristically exhibit low intensities, are perturbed, or assume an oscillatory pattern. Conversely, plaque-free segments are subjected to smooth laminar blood flow and high laminar shear stress, as documented in previous studies [[59], [60], [61], [62]]. These findings indicate that low and oscillatory shear stress play a pivotal and decisive role in the incipient development of atherosclerotic lesions, while high shear stress functions as protective mechanism, inhibiting their formation.

Situated in the innermost layer of blood vessels, the endothelium assumes a pivotal role as a vascular barrier to prevent harmful substances from infiltrating into the vessel wall. Abundant research has demonstrated that low and oscillatory shear stress possesses the capability to disrupt this protective barrier, which increases the endothelial permeability and facilitates the deposition of LDL and immune cells into the subendothelium, thereby contributing to the initiation of AS [63,64]. The cellular junctions between ECs are primary components for maintaining endothelial barrier. Studies have shown that tight junction proteins, such as Zonula Occludens-1 (ZO-1), Claudin-5, and Occludin, are downregulated by oscillatory shear stress through Nesprins/β-catenin pathway [65,66]. Adherens junctions have also been observed to respond dynamically to shear stress to regulate the morphology and orientation of ECs and modulate endothelial barrier [67]. While laminar shear stress stabilizes adherens junctions, oscillatory shear stress elicits the opposite effect, disrupting the barrier function and promoting atherogenesis [[68], [69], [70]]. The gap junction proteins predominantly consist of connexin43, connexin40, and connexin37, all of which also have been demonstrated to be involved in the influence of shear stress on AS development [[71], [72], [73], [74], [75], [76], [77]]. In addition to cellular junction, the endothelial glycocalyx is also regarded as a part of endothelial barrier. Research has shown that glycocalyx is involved in the transportation of LDL across the endothelium, operating simultaneously as a transport barrier and as a mechanosensitive molecule of shear stress, thereby mediating ECs apoptosis [78]. To summarize, it can be stated that disturbed shear stress is capable of enhancing endothelial permeability through multiple mechanisms, thereby instigating the deposition of LDL and the initiation of AS.

In addition to endothelial barrier disruption, the abnormal synthesis of NO is also a prominent manifestation of endothelial dysfunction during AS initiation. Decades ago, it was observed that the reduction of eNOS expression and NO production is correlated with the progression of AS [79,80]. In this context, supplementation with L-arginine, the primary precursor of NO synthesis, has been demonstrated to be beneficial in reversing the progression of AS [81]. Specifically, NO is regarded as an athero-protective molecule, being involved in mitigating vascular inflammation, as well as regulating cell proliferation, migration and apoptosis [[82], [83], [84]]. However, as previously expounded in Session 2, disturbed shear stress can influence the activity of eNOS and the production of NO in ECs through multiple mechanisms [[18], [19], [20],28,36]. Therefore, it is hypothesized that low and oscillatory shear stress may contribute to the initiation and progression of AS by impairing NO synthesis.

Progression of atherosclerosis: chronic inflammation and foam cell formation

Once LDL accumulates in the subendothelium, it is typically oxidized to form oxidized LDL (oxLDL). This oxidation initiates a localized inflammation, aggravating endothelial damage and attracting monocytes from the bloodstream into the subendothelial space [63]. Oxidative stress in ECs is considered as a unifying mechanism for many AS risk factors. By promoting excessive production of reactive oxygen species (ROS), oxidative stress contributes to the formation of oxLDL and endothelial inflammation [85,86]. There is increasing evidence regarding how abnormal shear stress converts into oxidative stress and contributes to the progression of AS. Under physiological conditions, laminar shear stress induces the expression of antioxidant genes in ECs, including superoxide dismutase (SOD) and glutathione S-transferase (GST) [87]. In contrast, low or oscillatory shear stress activates nicotinamide adenine dinucleotide phosphate oxidase (NOX) family, elevates ROS production and increases endothelial oxidative burden [[88], [89], [90]]. Therefore, disturbed shear stress contributes to the progression of AS by inducing oxidative stress and formation of oxLDL.

Disturbed shear stress pattern also plays a crucial role in facilitating monocytes infiltration, thereby forming foam cells within the subendothelium, a hallmark of early atherosclerotic lesions. In regions subjected to low and oscillatory shear stress, ECs are activated to upregulate the expression of adhesion molecules such as vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and E-selectin, which are critical for the initial tethering and firm adhesion of circulating monocytes [[91], [92], [93], [94]]. Concurrently, ECs also secrete more chemokines like monocyte chemoattractant protein 1 (MCP-1) and IL-8, directing monocytes toward the subendothelial space [63,95,96]. Consequently, monocytes and other leucocytes are recruited into the subendothelium, thereby forming foam cells and perpetual vascular inflammation. This endothelial activation driven by disturbed flow underscores the integral role of shear stress in promoting immune cell infiltration that underpin AS progression.

Beyond ECs and immune cells, VSMCs also take part in the progression of AS, which migrate into the subendothelial space, transmute into foam cells, and contribute to the constitution of fibrous cap [63,97]. Research has demonstrated that shear stress is involved in the modulation of VSMCs migration. In regions of high shear stress, VSMCs are aligned in a comparatively parallel manner with respect to the direction of shear stress, whereas in low shear stress regions, they are oriented perpendicularly to the shear direction, suggesting increased migration tendency [98,99]. Co-culture of VSMCs and ECs under static conditions also promotes VSMCs migration compared to a flow condition, accompanied with increased expression of transforming growth factor-β1 (TGF-β1) [100]. Therefore, shear stress contributes to AS progression through mediating VSMCs migration.

Advanced stage of atherosclerosis: plaque stability and rupture

When atherosclerotic plaques form and protrude into the vessel lumen, the localized arterial geometry is altered, thereby significantly changing the shear stress pattern in and around the plaques. It is well established that high shear stress typically arises at the proximal side of the stenosis, whereas low shear stress tends to occur at the distal side [101]. Interestingly, research has demonstrated that high shear stress correlates with greater plaque vulnerability and more extensive arterial wall remodeling compared with low shear stress [62,102,103]. Besides, most ruptured plaques are located in these proximal regions under high shear stress [104,105], which appears to contradict the general perception that high shear stress is protective for the endothelium. Wang et al. [106] proposed that angiogenesis at high shear stress sites contributes to increased plaque vulnerability. Specifically, high shear stress can induce ECM degradation and VSMCs apoptosis, resulting in mural cell and basement membrane loss around newborn microvessels. This leads to the leakage of microvessels, providing pathways for inflammatory cells and LDL particles to infiltrate the plaque. As a result, heightened inflammation and intraplaque hemorrhage may ensue, culminating in plaque rupture. Moreover, high shear stress itself may physically contribute to plaque rupture by exerting significant mechanical forces on structurally weakened areas of the plaque.

It is worth noting that in early and intermediate stages of AS, a moderately elevated shear stress can be beneficial. However, once an atherosclerotic lesion progresses to an advanced stage, the plaque’s internal structure and composition are profoundly altered, shifting the role of high shear stress from a protective factor to a catalyst for plaque destabilization. Consequently, evaluating local shear stress distributions is crucial for accurately predicting plaque rupture risk, elucidating the underlying pathophysiological mechanisms, and guiding clinical interventions aimed at stabilizing vulnerable plaques [107] (Fig. 3).

Fig. 3.

Effects of shear stress on different stages of atherosclerosis. Shear stress plays an important role in different stages of atherosclerosis (AS). Disturbed flow increases endothelial permeability, oxidative stress, VSMCs migration and endothelial activation in the initiation and progression of AS. High shear stress foster plaque vulnerability in advanced stage of AS. Image created with BioRender.com, with permission.

Other mechanical forces and atherosclerosis

For decades, low and oscillatory shear stress have been considered principle risk factors for AS, and have been widely employed to elucidate the preferential locations of AS lesions. However, emerging evidence suggests that other mechanical forces, such as hydrostatic pressure and cyclic stretch, may also play pivotal roles in the initiation of atherosclerotic lesions.

Ge et al. [108] proposed that elevated hydrostatic pressure, a factor that has long been overlooked, is a crucial determinant in the preferential sites of AS lesion initiation. According to Bernoulli’s equation ($P+\frac{1}{2}\rho v^2+\rho gh=constant$), regions predisposed to AS experience higher hydrostatic pressure couple with lower shear stress, attributed to lower blood flow velocity. Thus, this elevated hydrostatic pressure may be the actual aggravating factor, while low shear stress might serve merely as an apparent contributor. Compared to the traditional “low shear stress” theory, the hydrostatic pressure hypothesis presents significant merits. First, hydrostatic pressure exhibits a substantially higher order of magnitude compared to shear stress, offering a more compelling explanation for the progression of AS. Secondly, although veins and arterioles also encounter low shear stress due to diminished blood velocity, AS lesions predominantly manifest in large- and medium-sized arteries. This discrepancy can be attributed to the disparities in hydrostatic pressure across diverse vessel types, with hypertension (characterized by higher hydrostatic pressure) being a primary risk factor in AS. In line with this, in a study on PCSK9 transgenic minipigs under hypercholesterolemic conditions, Mashhadi et al. [109] demonstrated that increased cephalad hypertension induced by inflatable suprarenal aortic cuffs accelerated coronary AS by nearly fivefold, with the consistent development of fibroatheromas. This finding indicates that increased pressure per se facilitates AS progression. Further investigation into the underlying mechanisms revealed that hypertension enhanced the intimal accumulation of LDL and VSMCs in coronary arteries. Additionally, Swiatlowska et al. [110] identified that mechanical stimulation through hypertensive pressure alone was sufficient to induce lipid droplet accumulation and the transdifferentiation of VSMCs into foam cells. Other studies have shown that elevated hydrostatic pressure induces ECs apoptosis, impairs endothelial barrier integrity and triggers phenotypic switching of VSMCs in vitro and in vivo [58,111,112].

Concurrently, Wagner et al. [113] also postulated that cyclic stretch could potentially account for the initiation of AS. They observed that blood oscillations at specific arterial sites not only trigger a reduction in shear stress, but also increase the localized magnitude of cyclic stretch due to augmented pressure-dependent deformation of the vessel wall. Previous studies have demonstrated that pathological cyclic stretch disrupts endothelial barrier function [[114], [115], [116]], induces oxidative stress [113,117,118], and causes abnormal behavior in VSMCs [[119], [120], [121]]. These processes may be the mechanisms by which cyclic stretch contributes to AS development. However, there is still a dearth of in vivo animal models capable of directly substantiating the hypothesis that cyclic stretch initiates AS progression.

Together, these insights underscore that AS initiation may arise from a complex interplay of vascular mechanical forces, necessitating a more comprehensive understanding of local mechanical environments to fully elucidate the mechanisms underlying AS.

Vascular mechanical forces and hypertension

Hypertension, defined as persistently elevated arterial blood pressure, remains a significant risk factor for cardiovascular diseases. Despite longstanding research, its pathogenesis remains remarkably complex, driven by intricate interactions among multiple factors. Consequently, our current understanding of hypertension and its organ damage remains relatively limited, which in turn renders the complete cure or reversal of this condition unattainable. Traditional views of hypertension have largely focused on systemic factors, such as the renin-angiotensin-aldosterone system (RAAS) and autonomic regulation. However, a growing body of evidence underscores the importance of vascular mechanical forces in the pathogenesis and progression of hypertension.

The systolic and diastolic function of blood vessels bear a direct influence on blood pressure, which are modulated by factors such as vascular caliber, elasticity, and reactivity [122]. Notably, the calcium signaling pathway and the NO-nitric oxide sensitive guanylyl cyclase (NOsGC)-cyclic guanosine monophosphate (cGMP) pathway mediate vascular reactivity in a rapid and reversible manner, facilitating either vasoconstriction or vasodilation. In contrast, vascular remodeling, characterized by vascular lumen narrowing, wall thickening and elasticity loss, leads to irreversible structural and functional changes in the vasculature [123]. All of these mechanisms play indispensable roles in regulating vascular function, whose disruption may substantially contribute to the development and progression of hypertension. Moreover, oxidative stress and inflammation responses serve as upstream signals that can instigate or exacerbate these pathological alterations.

Therefore, the following section will concentrate on elucidating the effects of vascular mechanical forces on vascular function and corresponding signaling pathways, with the overarching goal of clarifying the relationship between vascular mechanics and hypertension.

Shear stress and hypertension

Shear stress contributes to the development of hypertension primarily by modulating the functions of endothelial cells, especially through the regulation of NO release—a critical mediator of vascular dilation. In healthy conditions, laminar shear stress elevates the activity of eNOS and boosts the production of NO, helping to maintain normal vascular tone and blood pressure in response to blood flow. Specific mechanosensors and mechanotransduction pathways involved in this process have been illustrated in Session 2, such as Piezo-1 and downstream P2Y₂/Gq/G11 signaling pathway [124] and adrenomedullin (ADM) secretion [125]. In contrast, the disturbed shear stress patterns or impairments in these mechanotransduction mechanisms can hinder flow-mediated vasodilation and predispose the vasculature to dysfunction. Consistent with these studies using mouse models, Paniagua et al. [126] demonstrated that hypertensive patients exhibit markedly impaired blood flow-induced vasodilation compared with normotensive controls, underscoring the link between shear stress-related vasodilatory dysfunction and high blood pressure. Collectively, these findings highlight the pivotal role of shear stress in preserving vascular health and emphasize how its dysregulation may drive the development of hypertension.

In addition to NO production, pathological shear stress has also been conclusively shown to exacerbate oxidative stress within ECs, which is a key mechanism for hypertension development. For example, in a study by Chao et al. [89], human umbilical vein endothelial cells (HUVECs) were subjected to low shear stress (3 dyne/cm²). Subsequently, an elevated expression of angiotensin II receptor was detected, which, in turn, led to a notable increase in intracellular ROS production. This finding was further substantiated in the inner wall of the mouse aortic arch, providing strong evidence for the relationship between pathological shear stress and oxidative stress. It also highlights that mechanical forces intersect with, and may amplify, well-established hypertensive mechanisms like the RAAS. The increased oxidative stress then triggers an elevation in blood pressure through multiple mechanisms. On the one hand, the excessive ROS, such as superoxide anion (O₂⁻), can react with NO to generate peroxynitrite (ONOO⁻), which reduces the bioavailability of NO and aggravates vascular dysfunction [127]. On the other hand, ROS can activate matrix metalloproteinases (MMPs), which facilitates extracellular matrix remodeling and prompts the migration of VSMCs. These combined processes lead to a reduction in vascular compliance, ultimately resulting in an increase in blood pressure [128]. Nonetheless, there is still a paucity of more direct and comprehensive evidence to firmly establish the logical continuum connecting shear stress and hypertension via the oxidative stress pathway. Moreover, compared to the extensive body of animal studies, research focused on human subjects in this particular domain remains relatively limited. This disparity in research focus limits our understanding of how these mechanisms translate to human pathophysiology.

In addition, investigations have revealed that both the in vitro functionality and the in vivo reendothelialization capacity of human endothelial progenitor cells (EPCs) are detrimentally affected in hypertensive and prehypertensive patients as compared to healthy individuals [[129], [130], [131]]. Notably, laminar shear stress has been demonstrated to enhance the in vitro and in vivo function of EPCs derived from hypertensive patients through GTPCH/BH4 [129] or β2AR/p38-MAPK/caspase-3 pathway [130,132]. These findings suggest potential therapeutic avenues for addressing endothelial dysfunction and repairment in hypertensive patients.

However, it is worth noting that the disruption of shear stress patterns typically occurs at specific sites in the vasculature, and whether such localized alterations in shear stress may translate to global impact on blood pressure remains uncertain. Understanding this relationship is crucial for fully grasping the pathophysiology of hypertension and potentially devising more targeted therapeutic strategies.

Cyclic stretch and hypertension

In the context of hypertension, the elevated blood pressure exerts augmented force on the vessel wall, consequently leading to pathologically intensified cyclic stretch in both ECs and VSMCs. The chronic and pathological elongation endured by these cells precipitates endothelial dysfunction and instigates vascular remodeling. These processes concomitantly augment vascular resistance, which, in turn, further escalates blood pressure, thereby establishing a vicious cycle. This vicious cycle not only exacerbates hypertension per se, but also amplifies the risk of developing cardiovascular diseases such as atherosclerosis and stroke. Therefore, comprehending the intricate vicious cycle interlinking hypertension and cyclic stretch is crucial to devise therapeutic strategies for hypertension.

Unlike shear stress, which acts primarily on ECs, pathological cyclic stretch promotes the progression of hypertension mainly by acting on VSMCs to facilitate vascular remodeling. The proliferation and migration of VSMCs play a crucial role in this process. Physiological cyclic stretch (10 %, 1 Hz) inhibits the proliferative effects of growth factors such as serum and platelet-derived growth factor (PDGF) through mechanism as blocking cell cycle progression and increasing the fraction of VSMCs in the G0/G1 phase [133]. Moreover, increased expression of angiotensin-converting enzyme 2 (ACE2) induced by cyclic stretch also suppresses VSMCs proliferation and migration [119], which indicates the potential interplay between mechanics and RAAS again. In contrast, in the presence of abnormally high cyclic stretch (such as under hypertension), the proliferation of VSMCs is significantly enhanced via multiple pathway [121,[134], [135], [136], [137], [138]]. Another vital aspect of vascular remodeling is the phenotypic conversion of VSMCs. Previous studies have shown that abnormal stretch induces a shift from the contractile to the synthetic phenotype in VSMCs [121,134,139,140]. The synthesis of extracellular matrix (ECM) components in VSMCs, such as collagen, hyaluronate, chondroitin 6-sulfate, and fibronectin, is also regulated by cyclic stretch [141,142]. In summary, in the context of hypertension, elevated cyclic stretch changes normal cell behavior and ECM synthesis of VSMCs, which contribute to vascular remodeling and further exacerbate blood pressure. Future research should focus on exploring potential therapeutic targets to alleviate or reverse vascular remodeling, as this could potentially unlock significant advancements in hypertension treatment.

Of note, immune cells are potentially implicated in the mechanisms through which cyclic stretch contributes to the progression of hypertension. A recent study demonstrated that neutrophils undergo increased NETosis upon exposure to hypertensive uniaxial stretch, which is mediated by the activation of TRPV4 and is further enhanced by coculture with ECs [143]. Such augmented NETosis, in conjunction with the accumulation of neutrophil citrullinated histone H3, impairs EC-dependent vascular relaxation and hereby exacerbates hypertension further. Moreover, hypertensive cyclic stretch has been founded to promote the differentiation of classical monocytes (CD14++, CD16-) into non-classical (CD14low, CD16++) and intermediate (CD14++, CD16+) monocytes, which subsequently actives innate and adaptive immunity responses [144]. This phenotypic alteration has been further corroborated in the circulating monocytes of hypertensive patients. These findings provide novel and valuable insights into the activation of the immune response and the ensuing inflammation in the context of hypertension.

Hydrostatic pressure and hypertension

The elevation of hydrostatic pressure represents a hallmark of hypertension, exerting greater pressure on ECs and VSMCs within the vessel wall. Despite its significant magnitude compared to shear stress and cyclic stretch, the role of hydrostatic pressure in the hypertension progression remains insufficiently understood. Emerging evidence suggests that hydrostatic pressure is not merely a passive consequence of elevated blood pressure, but may also be an active driver of hypertension exacerbation.

In vitro experiments have demonstrated that pure pressure overload, in the absence of shear stress or stretch, can induce the expression of c-Fos [145], an immediate early gene that rapidly responds to external stimuli and plays a role in regulating ECs and VSMCs behavior [146,147]. Single pressure can also promote DNA synthesis and cell proliferation in a pressure-dependent manner in VSMCs [148]. Further studies have highlighted its role in regulating the production of endothelin-1 (ET-1), a potent vasoconstricting substance. Two in vitro studies investigating the effect of hydrostatic pressure on ET-1 release reported conflicting results despite employing similar pressure levels (70 mmHg vs. 80 mmHg) [149,150]. In contrast, an in vivo study using ballon dilatation in patients with stable angina observed a significant increase in ET-1 concentrations across both the dilatation site and distal coronary segments, further supporting the role of hydrostatic pressure in ET-1 regulation [151]. Additionally, hydrostatic pressure has also been implicated in VSMCs proliferation [[152], [153], [154], [155]] and phenotypic switching [112,156], bothin vitro and in vivo, contributing to vascular remodeling. These processes collectively establish a self-perpetuating cycle, reinforcing hypertension progression over time.

It is important to acknowledge a fundamental limitation in current in vivo studies on hydrostatic pressure. Most studies have adopted hypertensive mouse models to simulate the high hydrostatic pressure environment. However, in the in-vivo setting, elevated hydrostatic pressure is invariably accompanied by increased cyclic stretch and shear stress, making it difficult to isolate hydrostatic pressure-specific effects. This confounding factor poses a significant challenge in identifying unique mechanosensors, downstream signaling pathways, and the precise functional consequences of hydrostatic pressure in vascular pathophysiology (Fig. 4, Table 2).

Fig. 4.

Effects of vascular mechanical forces on hypertension. Vascular mechanical forces contribute to hypertension progression collectively. Shear stress, cyclic stretch, and hydrostatic pressure under pathological conditions leads to vasoconstriction, vascular remodeling and inflammation. Image created with BioRender.com, with permission.

Table 2.

Representative in vivo and in vitro models for studying vascular mechanotransduction in hypertension.

Pathological process	Mechanical force	Model type	Description	Key findings	Representative reference No.
Impaired vasodilation	Low/oscillatory shear stress	Ex vivo, human	Increasing flow rate in isolated artery to induce shear stress	Induced NO-mediated vasodilation under higher shear stress	[126]
	High hydrostatic pressure	In vivo, human	Angioplasty in coronary artery	Increased ET-1 level in the distal coronary artery	[151]
Oxidative stress	Low/oscillatory shear stress	In vitro, HUVEC	A parallel flow chamber, 3 dynes/cm2	Increased ROS via AT1R/eNOS/NO	[89]
Vascular remodeling	High cyclic stretch	In vitro, VSMC	FX-5000 T FlexCell Tension Plus System, 18 % elongation	Increased VSMC proliferation	[138]
	High cyclic stretch	In vivo, mice	Aortic constriction surgury	Increased VSMC proliferation	[138]
	High cyclic stretch	In vivo, VSMC	A Flexercell Strain unit, 15 % elongation	Induced VSMC phenotypic change	[134]
	High hydrostatic pressure	In vivo, HASMC	A pressure-adjustable cell incubator, 200 mmHg	Two novel HASMC subsets identified	[112]

HUVEC, human umbilical vein endothelial cell; VSMC, vascular smooth muscle cell; HASMC, human aortic smooth muscle cell.

Interplay between vascular mechanical forces and chronic stress in hypertension

For decades, hypertension has been recognized as a disorder influenced by both psychological and physiological factors [157]. Chronic stress—a prolonged pathophysiological state induced by persistent exposure to adverse internal or external stimuli, including psychological stressors—results in sustained activation of the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system (SNS) [158,159]. This neuroendocrine overactivation leads to elevated levels of stress-related hormones, such as catecholamine and cortisol, as well as upregulation of RAAS, all of which are known to play significant roles in the development of hypertension [[160], [161], [162]]. However, the interaction between chronic stress and vascular mechanical forces in this process remains incompletely understood.

On one hand, vascular mechanical forces may act as intermediates that modulate stress-related signaling pathways in vessels. For instance, as mentioned above, it has been shown that low shear stress can enhance the expression of angiotensin II receptors [89], while physiological cyclic stretch could lead to increased expression of ACE2 [133], a counter-regulatory component of the RAAS. These findings suggest that pathological mechanical forces may amplify the RAAS activation during chronic stress. Furthermore, adrenergic signaling is also influenced by mechanical cues. Clements et al. demonstrated that cyclic stretch and intravascular pressure can interact with angiotensin II to modulate the mRNA expression of α1-adrenergic receptors in VSMCs, thereby regulating cell growth and proliferation [163]. Collectively, these studies indicate that abnormal vascular mechanical forces contribute to the exacerbation of neurohormonal activation under chronic stress, forming a potential mechanistic link to stress-induced hypertension.

Conversely, it is equally important to consider how neuroendocrine abnormalities influence the signal transduction of vascular mechanical forces. α1-adrenergic receptor, for example, has been implicated in mediating cyclic stretch-induced signaling through the Gαq/ERK pathway, leading to VSMCs proliferation [47]. Notably, both adrenergic receptor and angiotensin II type 1 receptor have been classified as mechanosensitive GPCRs, highlighting a bidirectional interface between hormonal stress responses and mechanical forces in vessels [164]. In addition, chronic stress-induced SNS activation produces direct hemodynamic effects, including elevated blood pressure and heart rate, which themselves impose increased hydrostatic pressure and cyclic stretch on the vessel wall [165,166]. These hemodynamic changes not only reflect the physiological manifestations of chronic stress but also act as mechanical triggers that further promote vascular remodeling and hypertension.

Taken together, the complex interplay between chronic stress and vascular mechanical forces represents a critical yet underexplored dimension in the pathophysiology of hypertension or other vascular diseases. Future research should aim to further elucidate the interaction of mechanobiology and chronic stress, yielding new insights into the etiology of hypertension.

Vascular mechanical forces and aortic aneurysm

Aortic aneurysm (AA) is characterized by permanent and irreversible localized dilation in the aorta, which is initially asymptomatic but can progress to life-threatening rupture or dissection over time. Based on the loc ation, aortic aneurysms are classified into thoracic aortic aneurysms (TAA) and abdominal aortic aneurysms (AAA). Although TAA and AAA exhibit different pathophysiological features, they share several common mechanisms during their progress, including gradual VSMCs loss, ECM breakdown, and persistent inflammation in the vasculature [167]. Vascular mechanical forces have been demonstrated to play a significant role in these processes.

Shear stress and aortic aneurysm

Aortic aneurysms commonly occur at sites where blood flow is disturbed, resulting in low or oscillatory shear stress, such as the curved thoracic aortic arch and infrarenal abdominal aorta proximal to the bifurcation [168]. Multiple studies have demonstrated that low shear stress is independently associated with increased expansion and rupture of AAA in human [[169], [170], [171]]. Nevertheless, some studies have suggested a potential association between high shear stress and aortic wall degradation [172]. Due to the complex hemodynamic environment within aortic aneurysm, more specific shear stress distributions and variations should be further investigated to determine their associations with aneurysmal progression.

An increasing number of studies indicate that endothelial dysfunction plays a crucial role in the development of aortic aneurysm, especially AAA. In a rat xenograft model, Franck et al. demonstrated that endovascular seeding with rat aortic ECs significantly prevented the formation of AAA, an effect associated with paracrine-driven reestablishment of a new aortic wall rich in VSMCs and ECM [173]. As illustrated previously, low or oscillatory shear stress elevates ROS levels and oxidative stress in ECs, thereby inducing endothelial dysfunction in AS [[88], [89], [90]]. Correspondingly, inhibiting the interaction between phosphorylated p47phox and p22phox in NOX2 complex effectively reduces oxidative stress and thus attenuates aneurysm progression in mice [174]. These findings suggest that aortic aneurysm and AS may share common mechanisms in shear stress-induced endothelial dysfunction, which may help explain why AS is a risk factor for aortic aneurysm. In addition, oscillatory shear stress may also contribute to the development of aortic aneurysm by influencing the activity of MMPs, which play a crucial role in breaking down the ECM and weakening the artery wall. The findings of Heath et al. demonstrated that oscillatory shear stress can induce the expression of miR-181b in HAVECs, which subsequently inhibits tissue inhibitor of metalloproteinases 3 (TIMP3), thereby increasing MMPs activity [167,175].

Cyclic stretch and aortic aneurysm

One significant characteristic of aortic aneurysm is a reduced number of VSMCs, which leads to the weakening of aortic wall. Accumulating evidence suggests that pathological cyclic stretch promotes VSMCs apoptosis and thus contributes to the development of aortic aneurysms. For example, Jia et al. reported that high cyclic stretch (18 %) significantly increases the expression of GRP78, ATF4 and CHOP in VSMCs, which are key endoplasmic reticulum (ER) stress markers. The ER stress subsequently promotes VSMCs apoptosis and degeneration, thereby contributing to thoracic aortic aneurysm and dissection [176]. In addition, overstretch can also cause the death of rat aortic smooth muscle cells (RASMCs) via the MAPK pathway, which can be inhibited by Azelnidipine and the upregulation of iNOS [177,178]. Other pathways involved in the cyclic stretch-induced VSMCs apoptosis include YAP1 and ADP/P2ry12, among others [179,180]. Collectively, these findings suggest that excessive cyclic stretch (such as that experienced in hypertension) induces VSMCs apoptosis through multiple pathways, thus promoting AA progression.

Beyond the loss of VSMCs, the degradation of ECM is another dominant feature in the pathology of aortic aneurysm. MMPs family play a crucial role in this process, among which MMP-2 and MMP-9 are the most studied. Studies have shown that cyclic stretch significantly increases the expression of MMP-9 and other inflammatory factors in rat vessels through activating MAPK pathway, thereby contributing to the progression of aortic dissection [181]. Further research indicates that both macrophages and VSMCs exhibit heightened MMP-9 expression under pathological cyclic stretch [182]. The increased production of MMP-2 has also been observed to relate with cyclic stretch. The Akt1/AP-1 and PDGFR-β/Akt signaling pathways are involved in this process [183,184].

It is noteworthy that the initiation of aortic aneurysm often coincides with abnormally high cyclic stretch due to the existence of hypertension, which is a significant risk factor for aortic aneurysm. However, as the aneurysm exists and progresses, the remodeling and calcification of the vessel wall increase vascular stiffness and alter the original mechanical properties of the vessel. Therefore, the cyclic stretch exerted on vascular cells decreases, as proved by the study of Ramella et al. that in the presence of aneurysm, aortic dilation decreases as the calcification index rises [185]. Subsequent studies revealed that abnormally low cyclic stretch is associated with increased ROS production and elevated MMP-9 expression, which underscores that low cyclic stretch can also drive AA progression in addition to high cyclic stretch. In other words, the mechanical environment is dynamic and complicated during the whole course of aortic aneurysm, and a comprehensive understanding of the mechanical environment is of great importance.

Clinical application value of vascular mechanical forces in aortic aneurysm

Currently, the primary criterion for deciding on the repair of AAA is the aneurysm diameter, with larger aortic aneurysms (diameter >5.5 cm) generally considered to have a higher risk of rupture and necessitate surgical intervention [186]. However, this single measurement criterion has its limitations, because some ruptures occur in aneurysms below this threshold, while others reach this size without rupturing [187]. With the advancement of vascular mechanics research, more attention has been paid to the clinical application value of vascular mechanical forces in aneurysms, particularly in predicting rupture risk and guiding individual treatment.

A growing number of studies have demonstrated the potentially significant value of shear stress in assessing the rupture risk of aneurysms. Boyd et al. [169] generated three-dimensional AAA geometry based on computed tomography angiography images of seven rupture AAAs and observed that rupture did not always occur at sites of maximal diameter but rather in regions with disturbed flow and low shear stress. The study of Teng et al. [188] further verified the correlation between aneurysm rupture and low shear stress by analyzing the differences of anatomical and hemodynamic parameters between ruptured and unruptured aneurysms. A meta-analysis containing 1257 aneurysms gave further evidence that decreased local shear stress may be an important predictive parameter of aneurysm rupture [189]. Multiple studies have then focused on computerizing shear stress features in aneurysms and establishing prospective validation cohorts to confirm the role of low shear stress in AAA expansion and future related events [171,190]. Therefore, by combining high-resolution imaging technologies (such as CT and MRI) with computational fluid dynamic models, clinicians can identify high-risk aortic aneurysms more accurately, thereby optimizing the timing and strategy of surgery, especially for those neglected smaller aneurysms with high rupture risk. Future research should focus on large-scale clinical validations to establish standardized applications of shear stress parameter in aortic aneurysm management (Fig. 5, Table 3).

Fig. 5.

The contribution of vascular mechanical forces to aortic aneurysm development and clinical applications. Pathological shear stress and cyclic stretch contribute to the development of aortic aneurysm by promoting VSMCs apoptosis, MMPs activation and ECM breakdown. Clinically, three-dimensional model reconstruction of mechanical diseases enable personalized rupture risk evaluation and treatment planning. Image created with BioRender.com, with permission.

Table 3.

Representative in vivo and in vitro models for studying vascular mechanotransduction in aortic aneurysm.

Pathological process	Mechanical force	Model type	Description	Key findings	Representative reference No.
Rupture-prone aneurysm	Low/oscillatory shear stress	In vivo, human	Generating 3D AAA geometry and calculating wall shear stress	Lower shear stress in rupture sites	[169]
VSMC apoptosis	High cyclic stretch	In vitro, VSMC	A mechanical strain unit (Flexcell 5000), 18 % elongation	Activated endoplasmic reticulum stress	[176]
	High cyclic stretch	In vitro, RASMC	A mechanical strain unit (STREX Inc, Osaka, Japan), 15 % elongation	Activated c-JNK/p38 pathway	[177]
	High cyclic stretch	In vitro, VSMC	A mechanical strain unit (Flexcell 5000), 20 % elongation	VSMC senescence via ADP/P2ry12	[180]
ECM degradation	High cyclic stretch	Ex vivo, mice	Isolated aorta, bio-function experiment system	Activated MMP-9 expression	[181]
	Low/oscillatory shear stress	In vitro, HAVEC	A cone-and-plate viscometer, 0 ± 5 dynes/cm2	Overexpression of miR-181b and activated MMPs	[175]

HUVEC, human umbilical vein endothelial cell; VSMC, vascular smooth muscle cell; HASMC, human aortic smooth muscle cell; ECM, extracelular matrix; HAVEC, human aortic valve endothelial cell; MMP, matrix metalloproteinase.

Conclusion

Vascular mechanical forces, comprising shear stress, cyclic stretch, and hydrostatic pressure, plays a pivotal role as regulators of vascular homeostasis. These forces exert their influences on the vessel wall in diverse directions and with distinct characteristics. Shear stress primarily influences the functions of ECs through blood flow dynamics, while cyclic stretch dictates the behaviors of VSMCs during pulsatile vascular expansion. These forces interact with ECs and VSMCs via mechanosensors such as Piezo-1, TRPV4, and the cellular junction structure, triggering a plethora of downstream signaling pathways that regulate proliferation, migration, apoptosis, phenotypic switching, and oxidative stress in cells. Whereas physiological forces help sustain vascular function, pathological forces disrupt vascular homeostasis, instigating the onset and progression of vascular diseases like atherosclerosis, hypertension, and aortic aneurysm. This review summarizes current understanding of mechanosensors, mechanotransduction pathways, and the cellular effects of vascular mechanical forces, highlighting their significance in the pathogenesis of vascular diseases. Insights derived from these studies not only enhance our comprehension of vascular mechanobiology, but also lay the foundation for devising innovative therapeutic strategies to prevent and manage vascular diseases.

Notwithstanding significant progress has been made in understanding vascular mechanical forces and their effects, substantial knowledge gaps remain. First, the mechanism underlying mechanosensing and signal transduction of these forces are still not fully understood. The exploration for new mechanosensors and signaling pathways is still in urgent need, especially those of cyclic stretch and hydrostatic pressure. Furthermore, the precise roles of know mechanosensitive molecules remain unclear, especially whether they function as primary sensor or downstream signaling components. Second, it is noteworthy that the in vivo environment is far more intricate than experimental settings, with multiple vascular mechanical forces coexisting and acting on the vessel wall simultaneously. The potential interplay and cross-regulation among different forces further complicates the landscape and warrants deeper investigation. Besides, the crosstalk between ECs and VSMCs under mechanical stimulation remains poorly characterized. And the roles of immune cells in responding to mechanical forces represents a novel and intriguing frontier. Understanding how these cell typers interact and contribute to vascular homeostasis and pathology is critical for uncovering the complex cellular network driving vascular diseases. Bridging these gaps and constructing a more comprehensive landscape for vascular mechanotransduction is essential for propelling the field forward.

Furthermore, increasing evidence has begun to uncover the genetic variability of mechanosensors and their potential relevance to inter-individual differences in vascular diseases susceptibility. For example, numerous Piezo-1 gene variants have been identified in association with human diseases, particularly involving the lymphatic system, veins and hematologic diseases [191]. In a large-scale cohort of 446,067 UK Biobank population, Cheng et al. identified 13 novel single nucleotide polymorphisms (SNPs) in Piezo-1 that were associated with primary hypertension [192]. In addition, Jiang et al. reported that a single-residue mutation in Piezo-1 (L322P) abolishes its mechanical activation by poking or membrane stretch, highlighting the functional consequences of specific missense mutations [193]. These findings suggest that genetic variations in Piezo-1 may contribute to differential vascular susceptibility by altering channel properties and mechanotransduction sensitivity. Similarly, polymorphisms of PECAM-1 have also been implicated in modulating monocyte adhesion to ECs, thereby influencing vascular inflammation [194]. Besides, the 53G > A substitution in the PECAM-1 gene has shown to attenuate shear stress-induced signaling and reduce atherosclerotic plaque formation [195]. Collectively, although such genetic variations may not directly cause vascular diseases, they likely modulate individual response to mechanical forces and contribute to disease development, which may help explain why certain individuals are more prone to vascular diseases. Future research should also investigate the genetic variability of other mechanosensors, such as TRPV4 and GPCRs, which remains relatively underexplored.

In terms of translational potential, vascular mechanics also offers opportunities for therapeutic innovation. Recent studies have explored pharmacological agents that modulate vascular mechanosensors and their downstream signaling networks [196]. For instance, Piezo-1 can be pharmacologically regulated by a variety of small molecules, including activators (e.g., Yoda1/2, CMPD15, Jedi1/2) and inhibitors (e.g., OB-1/2, benzbromarone, dietary lipids, Jatrorrhizine) [[197], [198], [199]]. Other examples include downstream pathway AMPK activators (metformin, AICAR) and YAP/TAZ inhibitors (statins, verteporfin) [196]. However, given the ubiquitous expression of these mechanosensitive molecules in multiple tissues, systemic drug administration poses a risk of off-target effects and toxicity, highlighting the importance for developing targeted delivery approaches. As a result, only a limited number of drugs targeting these molecules have so far entered clinical trials, including the selective TRPV4 inhibitor GSK2798745 (ClinicalTrials.gov identifier: NCT02497937). Beyond drug development, characterizing the mechanics environment of the lesion sites in atherosclerosis and aortic aneurysms may help predict the risk of complications, assess prognosis of the diseases, and guide individual clinical treatment [200,201]. Integrating the scientific breakthroughs into translational research could help revolutionize the current treatment of vascular diseases, which still needs a long way to go.

Looking ahead, the swift advancement of techniques such as artificial vessels and cardiovascular organoids holds prodigious potential for advancing vascular mechanics [202]. These tools offer three-dimensional viewpoints that more closely mimic in vivo conditions, facilitating precise manipulation and study of vascular mechanical forces, which may be able to bridge the gap of the lack of suitable models for studying vascular mechanical forces.

Compliance with Ethics

This article is a literature review and does not involve human participants, animals, or experimental studies. Therefore, compliance with ethics is not applicable.

Declaration of Generative AI and AI-assisted technologies in the writing process

Statement: During the preparation of this work the authors used ChatGPT in order to improve language. After using this tool/service, the authors reviewed and edited the content as needed and took full responsibility for the content of the publication.

CRediT authorship contribution statement

Shiwen Liu: Writing – original draft, Writing – review & editing. Jun Cai: Supervision, Conceptualization. Zhenzhen Chen: Supervision, Conceptualization, Writing – review & editing, Funding acquisition.

Funding

This work was supported by Beijing Research Ward Excellence Program, BRWEP (Project ID, BRWEP2024W012060100), National Natural Science Foundation of China (Project ID, 82330013, 82470461).

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Biographies

Shiwen Liu, a PhD student at Fuwai Hospital, Peking Union Medical College. Her research focuses on cardiovascular diseases, particularly in the pathogenesis and therapeutic strategies of hypertension. Received her bachelor’s degree from Sun Yat-sen University in 2024.

Jun Cai is the chief of the Beijing Anzhen Hospital affiliated to Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases. His research focuses on the pathogenesis, prevention and treatment of hypertension. In the past five years, he has published over 30 peer-reviewed papers as corresponding (include co-corresponding) author in international academic journals including N Engl J Med, Circulation, Circulation research, hypertension, etc.

Zhenzhen Chen, is an Associate Professor at Beijing Anzhen Hospital affiliated to Capital Medical University. Her research focuses on the pathogenesis and therapeutic targets of hypertension. She has published 16 papers as the first or corresponding author, holds an invention patent, and has received multiple research grants, including funding from the National Natural Science Foundation of China.