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Biomechanical factors as triggers of vascular growth

Imo E. Hoefer, Brigit den Adel, Mat J. A. P. Daemen
DOI: http://dx.doi.org/10.1093/cvr/cvt089 276-283 First published online: 10 April 2013


Haemodynamic factors influence all forms of vascular growth (vasculogenesis, angiogenesis, arteriogenesis). Because of its prominent role in atherosclerosis, shear stress has gained particular attention, but other factors such as circumferential stretch are equally important to maintain the integrity and to (re)model the vascular network. While these haemodynamic forces are crucial determinants of the appearance and the structure of the vasculature, they are in turn subjected to structural changes in the blood vessels, such as an increased arterial stiffness in chronic arterial hypertension and ageing. This results in an interplay between the various forces (biomechanical forces) and the involved vascular elements. Although many molecular mediators of biomechanical forces still need to be identified, there is plenty of evidence for the causal role of these forces in vascular growth processes, which will be summarized in this review. In addition, we will discuss the effects of concomitant diseases and disorders on these processes by altering either the biomechanics or their transduction into biological signals. Particularly endothelial dysfunction, diabetes, hypercholesterolaemia, and age affect mechanosensing and -transduction of flow signals, thereby underpinning their influence on cardiovascular health. Finally, current approaches to modify biomechanical forces to therapeutically modulate vascular growth in humans will be described.

  • Vascular growth
  • Biomechanics
  • Shear stress
  • Circumferential stretch

1. Introduction

The formation of a functional vascular network is a fundamental process in development, growth, and tissue maintenance. Principally, three different forms of vascular growth can be distinguished, differing in mechanisms, occurrence, and result. The predominant form that takes place almost exclusively during early embryogenesis is the formation of the primitive vascular plexus from angioblasts, known as vasculogenesis.1 The plexus subsequently grow by angiogenesis (hypoxia-driven de-novo formation of small calibre blood vessels by sprouting and tube formation by single endothelial cells within existing vessels). The vasculature is then modelled to the network of arteries, capillaries, and veins as it can be found in infants and adults. Angiogenesis prevails in adults, with a minor role for vasculogenesis.2 The growth of pre-existing interconnecting arterioles towards functional mature collateral arteries to bypass a vessel occlusion is referred to as arteriogenesis to distinguish it from hypoxia driven vessel growth.3

Mechanistically, arteriogenesis very much resembles arterial remodelling, but is restricted to vessels that interconnect different perfusion territories. Nevertheless, certain differences between arteriogenesis and arterial remodelling exist. Therefore, we will regard and discuss arterial remodelling and arteriogenesis as two different but closely related entities. Despite their differences, all mentioned processes share a common denominator, as all are vigorously influenced by biomechanical forces. In this review, we use the term ‘biomechanics’ to summarize the mechanical aspects of physiology. Hence, biomechanics is not limited to the various forces that act on the cells and non-cellular components of the vessel wall, but also encompasses the material properties of the vessels [extracellular matrix (ECM), elastin, collagen, etc.] which are subjected to these forces. Vice versa, the vessels' material properties can modulate the biomechanical forces and their effects. In cardiovascular research, the form of blood flow (i.e. turbulent vs. laminar) and the resulting shear stress (low vs. high vs. oscillatory) have gained much interest because of their prominent role in atherogenesis. Among the most important vascular factors that influence haemodynamics are the elasticity and the compliance of the vessel, which are largely determined by ECM components and their physiological and pathological adaptations. In this review, we provide an overview of the current knowledge on biomechanical forces and their involvement in the different forms of vascular growth and corresponding vessel type.

2. Interplay between haemodynamic forces, vessel structure, and vascular response

The most relevant haemodynamic forces that influence vessel size and morphology are shear stress, circumferential stress, and axial stress. Shear stress is the tangential force that a fluid (blood) exerts parallel to the vessel surface due to friction of the blood against the vessel wall. Circumferential stress describes the perpendicular force that the intraluminal pressure applies on the vessel wall. Axial stress in blood vessels is defined by the exerted longitudinal force, radius, and wall thickness and governs length adaptations. Although the role of axial stress has been known for more than a century,4,5 in vivo data are scarce, as the internal axial force cannot be measured directly in vivo.4,6 When axial stress is increased by stretching arteries without influencing shear stress or circumferential stretch, endothelial and vascular smooth muscle cells start to proliferate. This is accompanied by increased MMP activity and ECM deposition, resulting in compensatory growth in length in order to normalize axial stress.7 Shear stress under laminar flow conditions is defined by vessel diameter, flow velocity, and blood viscosity. Assuming constant viscosity and velocity, shear stress increases when vessel diameter is reduced. Generally, vessels enlarge in response to high shear stress to compensate for this increase and return it to normal levels.8,9 Circumferential stress is determined by vessel diameter, blood pressure, and vessel wall thickness (Figure 1). As a result, wall thickness has to increase when vessels expand or when blood pressure rises to keep the circumferential stretch constant.10,11 Theoretically, vessels could grow and remodel infinitely within the boundaries of the body as long as this leads to normalization of shear stress and circumferential stretch. However, mechanical adaptation properties of collagen and elastin in the vessel wall are limited. Hence, there is an optimal intercept limiting the extent of remodelling.12 From these basic principles, it becomes clear that any process that affects one of the mentioned parameters can induce significant modifications of vessel structure and geometry, which in return influences haemodynamics and biomechanics. The identity of the sensors (mechanosensing) that detect deformation of the cell, the transmitters of the resulting forces, and the subsequent biochemical signalling (mechanotransduction) yet remain to be fully uncovered. Notwithstanding an involvement of fibroblasts, the critical role in shear stress and circumferential stress sensing of endothelial and vascular smooth muscle cells (VSMC) is evident.13,14 These cells have the ability to respond to various micro- and macro-environmental stimuli, including mechanical stretch. High laminar shear stress is generally considered beneficial, as it protects from atherosclerosis15 and induces adaptive dilatation.16,17 Among the identified shear stress responsive elements (e.g. AP-1, NFκB, Egr-1),18,19 Krüppel Like Factor 2 (KLF2) has been shown to play a major role in maintaining vessel homeostasis.20 In contrast to many other shear-induced genes, KLF2 seems to be exclusively regulated by flow and has been suggested to regulate about one-third of all flow-induced genes,21 which encompass approximately 600 genes.18

Figure 1

Vessels are subjected to three different forms of stresses: shear stress τ, circumferential stress σθ, and axial stress σz. Shear stress depends on flow (Q), blood viscosity (η), and vessel radius (r). Circumferential stress is defined by the pressure (p) acting on the vascular wall, vessel radius (r), and the height (h) of the vessel wall. The force (F) that longitudinally acts on the vessel and the cross-sectional area of the vessel wall (A) are the determinants for axial stress, which leads to adaptations in vessel length.

Appropriate signal transduction requires normal, physiological function of the cellular transmitters, i.e. endothelium and VSMC. The vascular cells are interconnected via the cytoskeleton and integrins to the underlying ECM. As the ECM largely determines the vessel's stability and mechanical properties, improper assembly, structure, or breakdown of ECM components leads to disorders (e.g. Marfan syndrome) or vascular events (e.g. plaque rupture, aneurysm development, and rupture). Pathological processes (e.g. endothelial dysfunction) that lead to malfunctioning of any of these elements may thus also interfere with mechanosensing and perturb an adequate adaptation.

A second determinant of the response of the vascular wall to haemodynamic forces is the heterogeneity of the vessel's wall composition. Arteries and veins have three layers: the tunica intima, media, and adventitia. The intima (the thinnest layer) is formed by a single endothelial cell layer that is able to sense shear stress, glued together by a polysaccharide matrix and surrounded by a thin layer of connective tissue with the internal elastic lamina (circularly arranged elastic fibres). The tunica media consists of circular elastic fibres, connective tissue, and polysaccharides. The second and third vessel wall layers are separated by the external elastic lamina. The tunica media is (particularly in arteries) rich in VSMCs, which control the tone and diameter of the vessel. The tunica adventitia is the most prominent layer in veins and is composed of connective tissue. In larger blood vessels, the adventitia contains nerves and capillaries (vasa vasorum) that supply the vessel.

Arteries are subdivided into two different types, muscular and elastic, based on the presence of elastic fibres and smooth muscle cells in the tunica media as well as the composition of the internal and external elastic lamina. Large arteries (>10 mm diameter) are usually elastic, whereas smaller arteries (<10mm) tend to be muscular. Elastin contributes to the elastic properties of vessels at low to moderate blood pressure, while collagen is dominant at high pressures.22,23

The elastic compliance of the arterial system prevents abrupt falling of the arterial pressure and reduces the pressure pulse, pressure wave velocity (PWV), and the impedance faced by the heart. These factors influence the propagation of pressure and flow waves through the vascular tree. As a result, the energetic demand imposed on the vascular elasticity is a determinant of blood flow dynamics in the circulatory system. Ageing and diabetes mellitus (DM) reduce vascular compliance, and increase the PWV and the risk for stroke.24

3. Effect of biomechanical changes on vascular growth

Biomechanical factors are constantly subjected to changes in blood pressure, velocity, viscosity, and vessel structure. As such, they remain important moulding forces throughout the life. Increased flow triggers an increase in the vessel diameter in an attempt to keep shear forces at a constant level. Higher pressures induce increases in wall thickness to prevent excessive circumferential wall stretch.

3.1 Angiogenesis

Angiogenesis is a physiological process resulting in the growth of new blood vessels from pre-existing vessels. It is a potent natural mechanism to compensate for a reduction in blood supply to vital organs, namely by the formation of new capillaries to improve tissue oxygenation at the microcirculatory level.25 After birth, organ growth still requires angiogenesis.26 In adults, most blood vessels remain quiescent. Adult angiogenesis occurs, for example, during the menstruation cycle, in the uterus, and in the placenta. Angiogenesis is a remarkable process that occurs in an immediate response to hypoxia. It is important to note that these newly formed capillaries lack vascular smooth muscle cells.2 The role of haemodynamic forces in angiogenesis is controversial. Nevertheless, recent evidence suggests that increased skeletal muscle contraction during exercise may stimulate angiogenesis by increasing the production of nitric oxide and vasodilation of blood vessels. Furthermore, the role of biomechanical factors may differ depending on the type of angiogenesis. Intussusceptive angiogenesis, for example, is characterized by the formation of new vessels in contrast to the mere splitting of pre-existing ones (bridging) and has been shown to be significantly modulated by shear stress.27,28

4. Arterial remodelling

4.1 ‘Classical’ arterial remodelling and arterialization

The pivotal role of shear stress in determining arterial remodelling and diameter is illustrated by experimental and clinical data.29 Immediate changes in vascular tone are induced by acute changes in shear stress or blood flow through the activation of endothelial cells and the production of vasoactive agents. Chronic changes in flow lead to remodelling; more structural changes in arterial wall structure and function. A relatively simple model to induce an increase in shear in an existing artery without tampering with systemic haemodynamic parameters is by unilateral carotid artery occlusion. This induces a pressure drop downstream of the occlusion leading to a compensatory flow increase and a flow-induced enlargement of the diameter (outward remodelling) in the contralateral carotid, whereas the occluded artery experiences diminished flow and a diameter reduction (inward remodelling). Recent evidence from hypertensive rats showed enhanced arterial remodelling under high blood pressure conditions, indicated by an increased luminal and media area and a higher media/lumen ratio when compared with normotensive controls.30 Analysis of stretch, vessel diameter, and wall thickness indicated that despite higher circumferential wall stretch in the hypertensive animals, shear stress is the major determinant for vessel diameter in this model.31 This notion is further supported by the changes that high shear stresses are able to induce in endothelial cells. In vitro, endothelial cells exposed to high shear stress react with a gene expression pattern that promotes proliferation and matrix remodelling.3236

Various cell adhesion molecules (e.g. platelet endothelial cell adhesion molecule, PECAM-1) regulate the actual growth of the artery.37 Due to its central role in shear stress sensing, an appropriate endothelial cell function is necessary to ensure adequate reactions to alterations in blood flow. Hence, conditions accompanied by reduced endothelial cell function (endothelial dysfunction), such as ageing or DM, result in inadequate or reduced adaptation capacity.

Graft arterialization is a remodelling process induced by altered flow and pressure levels in veins when directly connected to the arterial network. It is a perfect example of the strong effects of biomechanical forces on vessel remodelling. Normally, veins experience only low flow velocities and low blood pressures, resulting in low shear stress and low circumferential stretch. Venous grafts are often used for coronary bypass surgery and dialysis. Once connected and functional, the venous endothelium of the graft is instantly subjected to the conditions of the arterial circulation. This results in morphological adaptations, including VSMC proliferation and EC phenotype changes. Previous studies have shown fundamental differences between arterial and venous endothelial cells which may explain the rigorous effects of the altered haemodynamics on these cells.38,39 While high shear stress usually protects from atherosclerosis and intimal hyperplasia, the opposite is occurring in the adaptation of venous grafts, where the vessel wall becomes hyperplastic to adapt to the increased circumferential stretch. The earlier mentioned differences in wall compositions between arteries and veins also contribute to this difference in adaptations to the high shear. As a result, the new conditions often lead to stenosis of the veins and closure of the graft within several years after surgery.40 In contrast, bypasses of arterial origin (e.g. internal mammary artery) have a much better 10-year patency rate, which might largely be attributed to the fact that the flow patterns essentially do not change.41 Whether these adaptations and differences are due to the endothelial phenotype or influenced by the accompanying atherosclerotic disease and its effects on mechanotransduction yet remain to be shown.

4.2 Arteriogenesis

As mentioned above, arteriogenesis (collateral artery growth) represents a special form of arterial remodelling. Anatomically, the substrate and the final product of both processes are almost identical: small arteries growing towards larger arteries. The main difference is the prerequisite of a pre-established connection between perfusion territories in arteriogenesis. Mechanistically, arteriogenesis and ‘classical’ arterial remodelling have many similarities.42 The most important driving force for both is a rise in shear stress as a result of increased blood flow, but the subsequent events deviate, motivating a separate description. Arteriogenesis, although mostly taking place in the presence of ischaemia/hypoxia, can occur under normoxic conditions.43 Collateral recruitment is triggered by a haemodynamically relevant stenosis in a larger artery that leads to a drop in peripheral perfusion pressure and hence an increased pressure gradient between perfusion beds. Once the pressure gradient is sufficient to overcome the high resistance of small calibre arteriolar connections between the beds, these anastomoses experience an increase in blood flow and shear stress. Subsequently, leucocytes adhere to the shear activated endothelium and migrate into the vessel wall.4446 Collateral flow in non-rodents models usually does not exceed 40% of flow in the native artery, even under growth factor or cytokine treatment.47 The most likely explanation is that once collateral arteries have been recruited and the conducted flow exceeds a certain level, the pressure gradient decreases, shear stress normalizes, and the trigger subsides. This is supported by studies in which the pressure gradient after femoral artery occlusion was artificially maintained at high levels by creation of an arteriovenous shunt between the distal stump of the occluded artery and the accompanying femoral vein, resulting in collateral flows that exceed normal femoral artery flow by far,48,49 supporting the essential role of shear stress in arterial remodelling and arteriogenesis. The effects of concomitant disorders and risk factors on collateralization are manifold and reviewed elsewhere.50 In the context of this review, a possible common denominator of diseases and endothelial dysfunction is discussed below.

5. Influence of concomitant disorders on mechanosensing and -transduction

The directly observable effects of endothelial dysfunction are to a large extent based on the reduced ability of the endothelium to produce and release NO. Apart from its vasoprotective role, NO is an important vasodilator and thus endothelial function is often measured by assessing pharmacologically or flow-induced vasodilatation, e.g. flow-mediated (vaso)dilatation (FMD).51,52 Usually, an impaired endothelial NO synthase (eNOS) expression that results in reduced NO levels is considered to be the main reason for endothelial dysfunction.53,54 Moreover, limited concentrations of the eNOS substrate, i.e. l-arginine, or a decreased availability of NO as a result of its interactions with reactive oxygen species (02) may end in endothelial dysfunction.55 In the long term, endothelial dysfunction and the accompanying lack of NO have been shown to reduce the vessels' ability to adequately adapt to changes in biomechanical forces. Of course, the effect of pathological conditions is not limited to mechanosensing and mechanotransduction. In particular chronic disorders such as hypertension, DM, or Alzheimer's disease but also ageing can induce haemodynamic and structural changes that lead to further vessel adaptations. Besides affecting cellular function, these conditions often affect the extracellular ECM components and can lead to collagen cross-linking, fragmentation of elastin, and calcification, increasing arterial stiffness. DM leads to formation of advanced glycation end products (AGE) that alter the mechanic properties of the vasculature like amyloid deposits do in intracranial vessels in Alzheimer's disease patients or elderly. In the following paragraphs, we illustrate the biomechanical consequences of a selection of disorders.

6. Diseases, biomechanical changes, and vascular growth

6.1 Diabetes mellitus

Types 1 and 2 DM cause an impairment of arterial endothelium-dependant relaxation, presumably owing the chronic hyperglycaemia. Insulin facilitates NO-dependant vasodilatations in vivo.56,57 DM also induces hypoxic conditions and thus angiogenesis (and plaque angiogenesis) is induced whereas arteriogenesis is impaired. Clinical and experimental evidence indicates that impaired (de novo) vascularization plays a key role in the impaired response to ischaemia in diabetic patients.58

Persistent hyperglycaemia leads to a non-enzymatic glycation of amino acids (Maillard reaction) and deposition of AGE, which can interact with the AGE receptor (RAGE). Laminar shear stress down-regulates RAGE expression and inflammatory responses in endothelial cells, whereas turbulent flow up-regulates RAGE.59 RAGE signalling results in modifications of the vascular structure through the cross-linking of several macro-molecules and collagen, culminating in accelerated graft remodelling in a mouse model of interposition vein grafting.60 Consistently, the presence of DM has been shown to influence collateral artery growth in several studies.61,62

Diabetic patients display increased red blood cell aggregation and blood viscosity, which potentially enhances shear stress and improves collateral growth. At the same time, DM reduces red blood cell velocity and flow rate, thereby decreasing shear stress.63 In combination with the altered mechanotransduction due to endothelial dysfunction, AGE formation, and RAGE signalling, there is a clear inhibitory role of DM on shear-induced collateral growth.62,64 Type 2 DM is furthermore often accompanied by hypercholesterolaemia in the context of the metabolic syndrome, which also reduces collateral growth and the responses to vascular growth factors by itself.65,66

6.2 Hypertension

As mentioned before, the elastic ability of large vessels allows them to accommodate the pulse pressure and significant volumes of blood under physiological conditions. Hypertension leads to a chronic increase in vessel wall shear stress.67 Thus, upon long-term exposure to high blood pressure, the structural and functional properties of vessels are modified to accommodate this change in pressure by vascular remodelling. This encompasses increased migration, proliferation, and apoptosis of ECs and VSMCs and ECM remodelling.68 Initially, elastic vessels can attenuate the effects of hypertension by their elastic properties. Prolonged hypertension leads to structural remodelling, altering the vessel wall shape and its composition (altered EC, VSMC, as well as ECM composition and structure, resulting in changes in the vessel wall/lumen ratio).69 This remodelling enables arteries to withstand the increased pressure load. Consequently, arteries become more rigid and have a reduced compliance than in their native state, which decreases their ability to dampen the cyclic changes in blood pressure.68 The progressive stiffening ultimately results in various clinical complications, such as left-ventricular hypertrophy.

Microvascular rarefaction, i.e. the gradual loss of capillaries and small arterioles, is frequently observed in arterial hypertension.70 A raised peripheral resistance is one of the consequences, leading to more severe hypertension and hypertension-induced organ damage as the adaptive response fails. As the amount of microvasculature is the result of the balance between de novo angiogenesis and microvascular regression, hypertension is characterized by both imbalanced angiogenesis and vascular remodelling.70

6.3 Ageing

With advanced age, large arteries dilate71 and their walls and the intima in particular, become thickened and stiffer.72 The balance between collagen and elastin in the vessel wall changes: collagen content increases, whereas the elastin fibres are reduced and fragmented due to an increased elastase activity with ageing. Overall, this leads to the development of dilated and less compliant vessels.

Moreover, it is generally accepted that both angiogenesis as well as arteriogenesis and arterial remodelling are delayed owing to the partial failure of several signal transduction pathways in ageing.73,74 Age is a well-known risk factor for cardiovascular complications and its effects on mechanotransduction of haemodynamic forces may further complicate matters. Although clinical evidence for a pure age effect is scarce, experimental data already indicated an age-dependant impairment of flow restoration after arterial occlusion more than two decades ago.9,75 How far this relates to reduced responses to changes in haemodynamics or hampered growth factor expression remains unclear.76 However, recent evidence suggests a role for KLF2 in age-dependant impairment of neovascularization.77 As stated above, KLF2 is mainly regulated by flow, pointing to a possible role of age in shear stress sensing and signalling. In addition, these changes are increased by disorders more common in elderly (DM, atherosclerosis) that share the common denominators of reduced EC function, vessel dilatation, and stiffer and less elastic arteries, aggravating the described effects of age.

6.4 Atherosclerosis

From the first decade of life onwards, atherosclerotic lesions develop at sites with low and/or oscillatory shear stress patterns (Figure 2). In short, compensatory expansive vascular remodelling occurs together with the development of atherosclerotic plaques mostly in regions with low shear stress patterns and, to a lesser extent, with turbulent flow15 to maintain lumen dimensions and ultimately lead vessel wall thickening and stiffening.78

Figure 2

Flow and shear patterns in different parts of the vascular tree. The inner curvature of curved arteries is usually subjected to low shear stress (blue), whereas the outer curvature experiences higher shear stress (purple). In regions, where vessels branch or bifurcate, turbulent flow (orange), or combinations of low and turbulent flow (spotted parts) depending on vessel diameter and angle can occur. High shear generally protects from atherosclerosis, whereas low shear and turbulent flow may lead to wall thickening and atherosclerotic plaque formation.

6.5 Therapeutic alteration of vascular biomechanics

Anti-hypertensive drugs, such as ACE inhibitors, can improve endothelial function and modulate ECM components leading to better mechanotransduction and reduced stiffness of large and muscular arteries.79 Similarly, angiotensin receptor blockers (e.g. valsartan, losartan) and calcium channel blockers (e.g. amlodipin) reduce arterial stiffness.80 Newer generations of anti-oxidant beta-blockers display vascular protective effects in experimental and human studies.81 The beta-blocker nebivolol significantly improves arterial stiffness in patients with coronary artery disease or hypertension and DM.82,83 Insulin-sensitizing drugs are widely described for patients with the metabolic syndrome and also display multiple pleiotropic effects such as an alteration in the inflammatory status and ECM turnover. In addition to their direct effects on the vascular wall components, lowering blood pressure and reducing hyperglycaemia also directly affect biomechanical forces (reduction of circumferential stretch) and improve disease-related interruption of appropriate signalling induced by, for example, increased AGE concentrations.

Cholesterol lowering drugs, in particular statins, are standard care for patients with increased cardiovascular risk. Statins are known for their additional, pleiotropic effects next to their lipid-lowering properties. They have been shown to be anti-inflammatory, promote VSMC migration and proliferation, and improve endothelial dysfunction,84 resulting in a better mechanotransduction of shear stress and wall stretch, which might explain the observed beneficial effects of statins on collateralization in patients despite the described anti-inflammatory effects.85,86

The increasing knowledge on vascular biomechanics will finally also provide new ways to modulate vascular growth by gene therapy, e.g. by better targeting of therapeutic agents or by mimicking the vascular response towards desirable haemodynamics. For example, the effects of different flow patterns and shear forces on adhesion molecule expression have been thoroughly investigated in vitro. This can be used to direct vehicles (e.g. microbubbles) to regions of interest by coupling them to antibodies directed against cell surface molecules (e.g. VCAM-1) expressed at specific sites.87 True gene therapy approaches that, e.g. alter intracellular cascades to mimic anti-atherosclerotic shear in vascular cells are conceivable, but not yet available. Indirectly though, the gene transfer of the serine/threonine kinase DYRK1A has recently been shown to improve endothelial function in hyperhomocysteinaemic mice.88 In view of the central role of MAP kinases in response to biomechanical stress,89 they have been postulated an interesting candidate for gene therapy, either directly or indirectly (e.g. via Nogo-B).90

Nevertheless, the recent insights in the molecular basis of vascular growth have already resulted in a change of treatment paradigms. For example, clinical studies aiming to improve adaptive vessel growth with growth factor or cytokine substitution remain largely disappointing.91,92 The results from the arteriovenous shunt models, though clinically not applicable, show that sustained increased shear stress can improve collateral-dependant flow to levels exceeding the normal ones. While downstream candidates have been identified and successfully tested experimentally, they are not yet ready clinical application.93 Probably, exercise will remain the most effective ‘therapy’ to increase shear stress, improve endothelial function, and promote collateral growth.94 Finishing second might be the mechanical intensification of shear stress by enhanced external counterpulsation. External counterpulsation enhances diastolic blood flow non-invasively by ECG-triggered inflation/deflation of pneumatic cuffs around the extremities, which are inflated during diastole, increasing diastolic flow in the coronaries and venous return. At the beginning of the systole, the cuffs are rapidly deflated, resulting in an improved myocardial perfusion and exercise tolerance and a decrease in angina symptoms.95,96 Experimental and first clinical data have provided promising results.97100 Whether the underlying mechanism depends directly on increased shear stress-induced collateralization or ‘merely’ an improvement of endothelial (dys)function remains to be seen, but may open new advances to improve collateral growth in patients.

7. Summary and conclusion

Vascular growth and remodelling is a constantly ongoing process required for vessel homeostasis and integrity. Growth factors and their receptors that control angiogenesis, vasculogenesis, arterial remodelling, or arteriogenesis have attracted much attention in the past decades, be it for stimulatory or inhibitory purposes. Recently, the fundamental role of biomechanical factors in the regulation of vascular growth has become more evident, leading to new perceptions and strategies for future clinical therapies. The mechanisms by which haemodynamic factors regulate vessel function are not limited to the vasculature, but may impact on many different organ systems and diseases (e.g. kidney disease, heart disease). Mechanical factors are crucial in virtually every aspect of vessel growth: shear stresses induce vasoregulatory mechanisms and diameter adaptations in order to normalize shear stress levels. Our perception of the endothelium being a passive, non-thrombogenic surface changed dramatically to that of a dynamically responsive vascular cell producing autocrine and paracrine factors regulated by local haemodynamic forces.

Moreover, it becomes more and more apparent that adaptations to biomechanical forces tune and limit the response of the vascular wall to biomechanical forces. Adaptive properties of the remodelling structures (elastin, collagen) are limited, meaning the adaptation process may ultimately fail, thus leading to disease progression.

Conflict of interest: none declared.


  • This article is part of the Spotlight Issue on: Biomechanical Factors in Cardiovascular Disease.


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