SPOTLIGHT REVIEW
Cardiovascular Research (2013) 99, 276–283
doi:10.1093/cvr/cvt089
Biomechanical factors as triggers of vascular growth
Imo E. Hoefer 1*, Brigit den Adel 2,3, and Mat J. A. P. Daemen 2
1
Laboratory of Experimental Cardiology, University Medical Center, G02.523, Heidelberglaan 100, Utrecht 3584 CX, The Netherlands; 2Department of Pathology, Academic Medical Center,
Amsterdam, The Netherlands; and 3Department of Pathology, University of Maastricht, Maastricht, The Netherlands
Received 11 December 2012; revised 2 April 2013; accepted 4 April 2013; online publish-ahead-of-print 10 April 2013
The article is part of the Spotlight Issue on: Biomechanical Factors in Cardiovascular Disease.
Abstract
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.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Vascular growth † Biomechanics † Shear stress † Circumferential stretch
----------------------------------------------------------------------------------------------------------------------------------------------------------This article is part of the Spotlight Issue on: Biomechanical Factors in Cardiovascular Disease.
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.
* Corresponding author. Tel: +31 88 755 7155; fax: +31 30 252 2693, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: [email protected].
Biomechanics in vascular growth
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
277
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, NFkB, 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 t, circumferential stress su, and axial stress sz. Shear stress depends on
flow (Q), blood viscosity (h), 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.
278
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
I.E. Hoefer et al.
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.32 – 36
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
279
Biomechanics in vascular growth
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.44 – 46 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
55
(02
In the long term, endo2 ) may end in endothelial dysfunction.
thelial 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 crosslinking, 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 endotheliumdependant 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 downregulates 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 crosslinking 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
280
I.E. Hoefer et al.
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
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.
6.3 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 agedependant 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
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,
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Biomechanics in vascular growth
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 ECGtriggered 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.97 – 100 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.
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