Flow (shear stress)-mediated remodeling of resistance
arteries in diabetes.
Emilie Vessi` eres, Mohamed Freidja, Laurent Loufrani, C´ eline Fassot, Daniel
To cite this version:
Emilie Vessi` eres, Mohamed Freidja, Laurent Loufrani, C´ eline Fassot, Daniel Henrion. Flow
(shear stress)-mediated remodeling of resistance arteries in diabetes.. Vascular Pharmacology,
Elsevier, 2012, 57 (5-6), pp.173-8. <10.1016/j.vph.2012.03.006>. <inserm-00768638>
HAL Id: inserm-00768638
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Flow (shear stress)-mediated remodeling of resistance arteries in diabetes
Emilie Vessières, Lamine M. Freidja, Laurent Loufrani, Céline Fassot, Daniel Henrion.
Dept of Integrated Neurovascular and Mitochondrial Biology
UMR CNRS 6214 – INSERM 1083,
University of Angers,
Address for correspondence:
Dr D. Henrion, Pharm.D., Ph.D.,
Dept of Integrated Neurovascular and Mitochondrial Biology
UMR CNRS 6214 – INSERM 1083,
Faculté de Médecine,
Tel: +32 41 73 58 45
Fax: +32 41 73 58 95/96
Web site: www.bnmi.fr
Shear stress due to blood flow is the most important force stimulating vascular endothelium.
Acute stimulation of the endothelium by shear stress induces a vasodilatation mainly due to
the release of nitric oxide (NO) among other relaxing agents. After a chronic increase in blood
flow (shear stress), the endothelium triggers diameter enlargement, medial hypertrophy and
improvement of arterial contractility and endothelium-mediated dilation. Shear stress-
mediated outward remodeling requires an initial inflammatory response followed by the
production of reactive oxygen species (ROS) and peroxinitrite anions, which activate MMPs
and extracellular matrix digestion allowing diameter expansion. This outward remodeling
occurs in collateral growth following occlusion of a large artery. In diabetes, an excessive
ROS production is associated with the formation of advanced glycation end-products (AGEs)
and the glycation of enzymes involved in vascular tone. The balance between inflammation,
AGEs and ROS level determines the ability of resistance arteries to develop outward
remodeling whereas AGEs and ROS contribute to decrease endothelium-mediated dilation in
remodeled vessels. This review explores the interaction between ROS, AGEs and the
endothelium in shear stress-mediated outward remodeling of resistance arteries in diabetes.
Restoring or maintaining this remodeling is essential for an efficient blood flow in distal
EDHF: endothelium-derived hyperpolarizing factor; FMD: flow-mediated dilation; NO: nitric
oxide; ROS: reactive oxygen species; ONOO-: peroxinitrite anion; eNOS: endothelial NO-
synthase; FMD: flow-mediated dilation; MMPs: metalloproteases; ECM: extracellular matrix;
AT1/2R: angiotensin II type 1 or 2 receptor.
Key words: Endothelium, resistance arteries, mechanotransduction, remodeling, shear stress
The endothelium plays a central role in vascular homeostasis and allows the
vasculature to adapt to the local need of each tissue. In response to various stimuli, the
endothelium produces nitric oxide (NO) from the amino acid L-arginin that induces the
relaxation of the muscular layer and vascular dilation. In resistance arteries, the endothelium
produces vasodilator agents such as prostacyclin and EDHF as well as vasoconstrictor agents
such as angiotensin II, thromboxan A2 (TxA2) and endothelin-1. Pulsatile blood flow
produces three types of hemodynamic forces: a) hydrostatic pressure generated by the liquid,
aa) cyclic stretching and aaa) shear stress. Stretching is a cyclic distension of the wall caused
by a transmural pressure gradient and depends on thickness of the vessel wall, its composition
and the degree of contraction of smooth muscle. The main effect of cyclic stretching is the
induction of oxidative stress in endothelial cells. On the other hand, shear stress results from
the frictional forces exerted by blood flow directly on endothelial cells and is determined by
blood flow, blood viscosity and vessel diameter. Acute changes in blood flow or shear stress
induce immediate changes in tone by activating endothelial cells, which produce vasoactive
agents. In response to a chronic change in flow, the endothelium induces deeper changes in
arterial wall structure and function usually referred as remodeling.
Diabetes is increasing worldwide in industrialized as well as in developing countries,
posing a major challenge to global human health. Cardiovascular diseases are the major cause
of morbidity and mortality in type 2 diabetes due to arterial structure and functional alteration.
The most important damages observed in diabetic patients are hind limb ischemia and end
organ damages . Vascular damages associated with diabetes could be explained in part by
the reduction of small resistance arteries capacity to adapt in response to chronic changes in
blood flow. Indeed, shear stress-mediated remodeling of small resistance arteries is essential
for collateral growth following arterial occlusion and for revascularization of ischemic tissues,
a key problem in diabetes.
This article focuses on the role of the endothelium in flow-mediated remodeling of
resistance arteries and on the changes induced by metabolic syndrome and diabetes. Indeed,
local blood flow supply is a critical issue in metabolic disorders associated with overweight
B. Control of microvascular tone and role of shear stress
The vasculature consists of large arteries branching out into smaller and smaller
vessels terminated by capillaries. Capillaries irrigate tissues and are connected to larger veins
via venules. Structural and functional differences between large arteries and arterioles are
obvious when comparing the aorta to pre-capillary arterioles. Indeed, differences in blood
pressure, pulsatility, and organ or tissue specificity induce a specialization of vascular cells.
Changes in the hemodynamic environment induce short-term responses and structural
adaptation of the vascular tree, thus allowing an optimal tissue perfusion [2,3]. Small arteries
having the most important influence on local blood flow are called resistance arteries. These
arteries are submitted to chemical and neuro-hormonal influences in addition to the
continuous effect of the mechanical factors generated by the blood stream, mainly pressure
and flow. Pressure induces a rapid and sustained vasoconstriction called myogenic tone [4-6].
Myogenic tone represents a tonic arteriolar contraction facilitating the action of the other
vasoactive systems, mainly the sympathetic and the renin-angiotensin systems, through a
synergistic mechanism or potentiation, controlling the sensitivity to calcium of the contractile
apparatus [7-12]. This potentiation relies mainly on the activation of the RhoA-Rho-kinase
pathway  leading to a higher level of filamentous actin in the cytosol . On the other
hand, blood flow produces shear stress, which stimulates the endoluminal surface of the
endothelium. Flow (shear stress)-mediated dilation (FMD) represents a basal vasodilator
stimulus activating continuously the endothelium. Together with myogenic tone, FMD
determines a basal tone over which other vasoactive systems may act more efficiently. Shear
stress induces the production of nitric oxide (NO), prostacyclin and endothelium-derived
hyperpolarizing factor (EDHF) as well as the production of vasoconstrictor agents such as
endothelin-1 and angiotensin II . A reduction in FMD is the hallmark of endothelial
dysfunction and it is becoming more and more important in the detection, the follow-up and
even the prevention of vascular disorders in a growing number of diseases described in recent
review articles [16-18]. As shown in a recent review article , a change in flow (shear
stress) induces a complex response of the endothelial cell with the involvement of the
extracellular matrix, the primary cilia and membrane-associated proteins, mainly ionic
channels and adhesion molecules. The signal may also be transmitted to surrounding cells
through the cytoskeleton and the integrins. Each may be affected by diabetes, especially in
response to chronic changes in flow. Acute responses to flow seems to be rather affected by
the excessive oxidative stress occurring in diabetes leading to reduced NO bioavailability.
To assess the endothelial dysfunction in patients, a flow-mediated dilation method can
be carried out noninvasively with ultrasonography on the brachial artery . Thus, it has
been demonstrated not only an alteration in FMD [21,22] but also carotid intima-media
thickness and arterial stiffness increases even before the onset of type 2 diabetes .
Interestingly, the reduction in FMD is inversely related to the extent of hyperglycemia .
Nevertheless, the underlying patho-physiological mechanisms remain to be fully elucidated.
A complete understanding of the association between arterial alterations is critical for the
primary prevention of diabetes-associated vascular disorders. Diabetes increases substantially
the risk of developing ischemic cardiovascular events. Consequently, in diabetic individuals,
there is a high incidence of critical limb ischemia and lower extremity amputation. It is most
likely that impaired compensatory responses in the setting of acute or chronic ischemia in
diabetes are responsible for this poor clinical outcome. Besides a reduced vasodilatation,
diabetes is also associated with a decreased revascularization as evidenced in experimental
models [24,25]. Post-ischemic revascularization involves several mechanisms. Following
occlusion of a large artery, arterial blood flow is redirected through adjacent preexisting
collateral smaller arteries. In addition, hypoxia induces angiogenesis in the ischemic area.
Thus, the consequent increase in shear stress induces outward remodeling of the preexisting
collateral arteries . As vasodilatation is the initial step leading to outward remodeling, the
impairment in FMD observed in diabetes is most likely associated with impaired remodeling
leading to decreased revascularization. As described below, flow-mediated outward
remodeling is inefficient in diabetes and this defect may be in part responsible for the
hypertrophic remodeling this disease. Indeed, in both type 1 and type 2 diabetes, the arterial
wall is hypertrophic, at least in large blood vessels. Hypertrophic remodeling of subcutaneous
small arteries is also present in non-insulino-dependent diabetes as evidenced by an increase
in tunica media to internal lumen ratio. This remodeling is equivalent to that observed in
hypertension and associated with reduced FMD . This remodeling in small resistance
arteries in diabetes might be due to a higher inflammatory state linked to oxidative stress .
C- Mechanotransduction of flow (shear stress): chronic responses
1- Microcirculatory adaptation to chronic changes in blood flow
Chronic increases in blood flow induce arterial wall remodeling allowing tissues and
organs to adapt to a new hemodynamic environment. Arterial remodeling is defined as a
change in structure and function of the component of the wall, mainly the endothelium and
the muscle. In resistance arteries chronic increases in wall shear stress induces a remodeling
triggered by endothelial cell and consisting of a diameter enlargement aiming at normalizing
shear stress. This is associated with a compensatory hypertrophy normalizing circumferential
strain due to dilation and with improvement of endothelium-mediated dilation due, at least in
part to increased eNOS expression level [29-32]. This remodeling is involved as a response to
an increase in the metabolic need of different tissues during growth, following exercise
training or during pregnancy. Flow-mediated remodeling allows a better perfusion of the
downstream-located tissues. It is also expected when a collateral growth is needed after
ischemia. Substantial evidence shows that this collateral growth is impaired in the presence of
risk factors such as aging [31,33,34], metabolic syndrome [32,35], hypertension  or
Remodeling of resistance arteries due to high blood pressure has been widely investigated
[5,38]. On the other hand, reorganization of the arterial wall after chronic changes in blood
flow has been mainly studied in large arteries allowing a better understanding of diseases such
as atherosclerosis and aneurysms [39,40]. In the microcirculation, the occurrence of
remodeling is not clear and the mechanisms involved not yet fully described. Nevertheless, in
ischemic and metabolic diseases, flow-mediated remodeling of resistance arteries has a key
role besides angiogenesis and arteriogenesis [41,42]. After chronic exercise training, which
increases chronically blood flow, resistance arteries diameter increases in association with an
enhanced endothelial capacity to produce NO and prostanoids . Similarly, chronic
vasodilator treatments increase local blood flow with consequences on wall structure and
function similar to those due to exercise training . In order to investigate selectively
changes in wall structure and function occurring in response to blood flow variations, a model
has been developed in the mesenteric vascular bed. In short, arteries are alternatively ligated
so that they are submitted to low, high or normal blood flow without changes in blood
pressure, hormonal environment or body mass [45,46]. In this model, chronic increases and
decreases in blood flow induce outward and inward arterial remodeling, respectively. Arterial
wall remodeling is accompanied by a compensatory change in medial mass, which restores
circumferential wall stress [46,47]. A chronic increase in blood flow also increases the
dilatory capacity of the endothelium, especially in response to shear stress or vasodilator
agonists [29,32,48-50]. Endothelial cells from high-flow arteries express more eNOS than
control arteries [30,32,51] and the production of NO is critical for the diameter enlargement
. Indeed, NO acts in association with reactive oxygen species (ROS) to form peroxinitrites
(ONOO-), which in turn activate MMPs; as shown in the carotid artery  and in the
mesenteric circulation .
Arterial wall hypertrophy associated with the increase in diameter involves the local
production of angiotensin II as either angiotensin I converting enzyme inhibition or
angiotensin II type 1 receptor blockade prevented the hypertrophy without affecting the
increase in diameter . This is in agreement with previous works showing the involvement
of the local renin-angiotensin system in the vascular response to shear stress [15,55,56].
Intriguingly, ROS production and ERK1/2 are involved in both outward remodeling due to
high flow and in inward remodeling due to low flow. Indeed, the inflammatory response is the
central link between the two type of response as previously demonstrated by Bakker et al.
 who have shown that the inflammatory response triggers the remodeling process but the
type of response (outward or inward) is directed by vascular tone. Finally the last step also
relies on a common mechanism. Indeed, when outward or inward remodeling is established,
associated to a normalization of shear stress, tissue-transglutaminases stabilize the arterial
wall [58,59]. Among the nine members of the transglutaminase family, three are expressed in
the vasculature: type 1, type 2 and factor XIII. Cross-linking of proteins is the main feature of
transglutaminases providing mechanical strength to tissues. Their involvement in other
processes in vascular biology is more recent. Their role in endothelial barrier function or
small artery remodeling is summarized in a recent review article .
Figure 1: Changes in blood flow, decreases or increases, induce an inflammatory response
responsible for oxidative stress and synthesis of angiotensin II. This results in activation of
metalloproteases (MMPs) that cause a partial dissociation of the extracellular matrix (ECM). The
next step depends on the basal stimulus inducing the remodeling. In arteries subjected to increased
flow, the endothelium is over-stimulated and produced more NO, which increases arterial
diameter. In arteries subjected to low flow, the endothelium is under-stimulated and produces less
NO. Thus NO counteracts less angiotensin II that can then contract the artery. In all cases, the
remodeling is stabilized when the diameter reaches a level allowing normalization of shear stress.
In the artery submitted to high-flow, activation of angiotensin II type 1 receptor and MAP kinase
ERK1/2 induces a compensatory hypertrophy.
2 - High blood flow-mediated-remodeling in pathological conditions
2.1. Vascular ageing and oxidative stress
High flow-mediated remodeling is impaired in physiological aging in the rat [31,33].
Nevertheless, increasing blood flow in two-year old rats remains able to induce hypertrophy
 and to improve endothelium-mediated dilation . A recent study has also shown that
an antioxidant treatment with either tempol or apocynin reverses age-related collateral growth
impairment, suggesting that an excessive oxidative stress opposes diameter enlargement .
As both hydralazine and the antioxidant drugs tested are potentially vasodilator, it remains
possible that the threshold for flow sensing is shifted in aging toward larger shear stress
values and that any drug increasing shear stress will be efficient. This hypothesis remains to
be demonstrated. An excessive oxidative stress might oppose remodeling in pathological
situations. Nevertheless, induction of endothelial cell tube formation in vitro and coronary
collateral growth in vivo requires a specific intracellular concentration of ROS. ROS levels
below and above this optimal range prohibit coronary collateral development and endothelial
cell tube formation . This is in agreement with our previous observation demonstrating
the essential role of ROS in flow-mediated arterial enlargement  and with another study
showing that ROS inhibit the same remodeling in young spontaneously hypertensive (SHR)
rats  as well as in old normotensive rats .
2.2. Obesity without diabetes or with moderate diabetes
In the Zucker rat, a model of metabolic syndrome with obesity associated with moderate
diabetes and hypertension, flow-mediated diameter enlargement occurs without improvement
of endothelium-mediated dilation. Indeed, in high-flow vessels, FMD is worsened compared
to control arteries associated with a reduced implication of NO . This is in agreement with
previous studies showing in Zucker obese rats, an endothelial dysfunction in several vascular
beds  associated with a reduced NO concentration  and an increase of vascular
oxidative stress , which is associated with eNOS uncoupling . Thus, even if the
“structural” remodeling occurred after a chronic increase in blood flow, endothelium-
dependent dilation was not improved but further deteriorated. This could support elevated
vascular resistance, moderate hypertension or limited oxygenation of host organs. In addition,
the endothelial alteration following chronic rise in blood flow might have negative
consequences in the long-term when patients suffering metabolic syndrome are recommended
to practice exercise or are given vasodilator treatments. Of course, these studies were
performed in rat mesenteric arteries and this conclusion may not entirely apply to other
vascular territories, as exercising, in controlled conditions, has been proven efficient in obese
patients. Indeed, regular and moderate training has pleiotropic effects and consequently does
not only affect the vasculature .
Figure 2: High flow-mediated remodeling in a rat model of metabolic syndrome. A chronic increase in
blood flow induces inflammation and oxidative stress. This latter added to pre-existing oxidative stress
due to obesity and moderate diabetes induces an exaggerated hypertrophy of the arterial wall and an
additional deterioration of endothelial-dependent dilation, however activation of metalloproteases
(MMPs) by peroxinitrites (ONOO) persists and causes a partial dissociation of the extracellular
matrix (ECM). Green arrows refer to physiological remodeling and red arrows point out the effect of
metabolic syndrome on the process.
In old Zucker rats (in blue), oxidative stress is higher than in young rats. As a consequence,
endothelium-mediated dilation is more severely impaired. Despite important reduction in NO
availability, the production of prostacyclin (PGI2 produced by COX2) induces vasodilatation
sufficient to increase arterial diameter.
EC=endothelial cell; SMC=smooth muscle cell.
Paradoxically, high flow-mediated remodeling remains fully efficient in one-year old obese
Zucker rats, by contrast with control rats in which remodeling is impaired as described above.
Nevertheless, even though diameter enlargement occurred, endothelium-dependent dilation
was strongly impaired in association with a larger oxidative stress than in other arteries from
Zucker rats . Indeed, the moderate increase in oxidative stress associated with a chronic
rise in blood flow occurs above a pre-existing oxidative stress and consequently, NO-
mediated dilation is further decreased. Although NO production is strongly reduced in old
Zucker rats, remodeling occurred, due to a COX2-dependent production of vasodilator
prostanoids, possibly prostacyclin. Indeed, the pharmacological treatment of rats with
celecoxib, a COX2 blocker, inhibited diameter enlargement . COX2 is expressed in old
Zucker rats mesenteric arteries together with an excessive oxidative stress . This
maintenance of a larger arterial diameter in old Zucker was not observed in other vascular
territories where arterial narrowing usually occurs . Interestingly, mesenteric blood flow
is higher in obese Zucker rats than in lean animals [72,73]. Thus local inflammation in obesity
might preserve high mesenteric blood flow, which may participates to the development of
2.3. Flow-mediated remodeling of resistance arteries and diabetes
On the opposite, we found in young Zucker diabetic fatty (ZDF) rats that flow-mediated
arterial enlargement is impaired . Nevertheless, in diabetic animal, remodeling may also
be impaired due to excessive advanced glycation end products (AGEs) accumulation .
The flow-sensing process is probably not sufficiently impaired to explain this observation as
in response to the chronic increase in flow both eNOS and caveolin-1 expression were
enhanced similarly to control lean rats. This observation rules out, at least in part, a possible
reduction in flow sensing by advanced glycation end products (AGEs), which have been
shown to reduce the activity of several processes in type 2 diabetes. AGEs have been reported
to alter the matrix proteins collagen, vitronectin, and laminin, through AGE-AGE
intermolecular covalent bonds, or cross-linking [76,77]. The absence of remodeling is
probably not the consequence of the overweight observed in ZDF rats as in obese Zucker non-
diabetic rats outward remodeling occurred normally . Thus, it is most likely that
extracellular matrix digestion is affected by AGEs and that this defect prevents remodeling.
This assumption is supported by a study showing that, in diabetes, revascularization following
femoral artery ligation is reduced by AGE formation. Indeed, the authors have shown that
AGEs reduce extracellular-matrix degradation by MMPs and subsequently abrogates the
angiogenic process needed for revascularization . This study has also shown that
abrogating AGEs formation with aminoguanidin restored angiogenesis in diabetic (type 1,
induced by streptozotocin) rats. In diabetic rabbits (type 1, induced by alloxan), growth of
collateral arteries was estimated by the measurement of arterial size using X-ray radiography
. This work suggests that reduced collateral arterial growth observed in diabetes is
associated with a decreased monocyte chemotaxis and growth factor signaling. So far, it
seems that the presence of AGEs is the main determinant of the altered remodeling found in
diabetes, more than the type of diabetes, type 1 or type 2. Nevertheless, no study has yet really
compared the two types of diabetes using a similar model.
In isolated arteries of ZDF rats, abnormally high oxidative stress dramatically reduces
endothelium (NO)-mediated dilation in arteries submitted to high blood flow mainly because
of NO scavenging and eNOS uncoupling . In ZDF rats, besides NO scavenging by
reactive oxygen species, thromboxanA2 generated by COX-2 also reduces endothelium-
mediated dilation .
Figure 3: High flow-mediated remodeling in a rat model of type 2 diabetes. A chronic increase in
blood flow induces inflammation and oxidative stress. This latter added to pre-existing oxidative stress
due to obesity and moderate diabetes induces an exaggerated hypertrophy of the arterial wall and an
additional deterioration of endothelial-dependent dilation. In addition, activation of metalloproteases
(MMPs) by peroxinitrites (ONOO) might be prevented by AGEs and consequently extracellular matrix
(ECM) would not occur, thus preventing diameter expansion. Green arrows refer to physiological
remodeling and red arrows point out the effect of diabetes on the process. Alternatively,
cyclooxigenase-2 (COX-2) derived thromboxan A2 (TxA2) might also reduced diameter enlargement
and endothelium-mediated dilation.
Shear stress-mediated remodeling is essential for collateral growth following arterial
occlusion and for revascularization of ischemic tissues. It depends on the equilibrium between
the production of NO and of that of superoxide anions. In diseases such as diabetes and
obesity, an excessive ROS production disrupts this equilibrium and thus the capacity of
resistance arteries to adapt to chronic increases in blood flow. In diabetes, AGEs increase the
dysfunction and, added to ROS prevents remodeling and reduces endothelium-mediated
dilation. Fighting both AGEs formation and oxidative stress represents a reasonable way to
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