Am J Physiol Heart Circ Physiol 288: H1044 –H1050, 2005;
doi:10.1152/ajpheart.00773.2004.
New Developments in
Resistance Artery Research: From Molecular Biology to Bedside
8TH INTERNATIONAL SYMPOSIUM ON RESISTANCE ARTERIES
Marriage of resistance and conduit arteries breeds critical limb ischemia
Paul Coats and Roger Wadsworth
Department of Physiology and Pharmacology, University of Strathclyde, Glasgow, United Kingdom
Submitted 30 July 2004; accepted in final form 13 September 2004
microvessels; nitric oxide synthase; cyclooxygenase; inflammation;
vascular diseases
CRITICAL LIMB ISCHEMIA (CLI) represents ischemia of such severity as to compromise lower limb function and endanger
survival of the affected leg(s). It occurs when the supply of
blood to the capillary beds is less than that required to sustain
surrounding tissue viability. CLI has an annual incidence of 1
in 1,000 population and is associated with a significant increase
in morbidity and reduced life expectancy, and patients generally have a poor prognosis (40). The primary cause of CLI is
atherosclerotic lesions within the large communicating arteries.
The resistance to blood flow produced by these lesions results
in a critical reduction in perfusion pressure to the distal portion
of the affected leg(s). Consequently, blood flow to the distal
part of the leg(s) results in ischemia and, consequently, ischemic pain, tissue necrosis, and gangrene (51).
Address for reprint requests and other correspondence: R. M. Wadsworth,
Dept. of Physiology and Pharmacology, Institute for Biomedical Sciences,
Univ. of Strathclyde, Taylor St., Strathclyde Univ., Glasgow G4 0NR, UK
(E-mail: [email protected]).
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In time, chronic ischemia, as a primary consequence of
macrovascular disease, results in a number of structural and
functional adaptations to the microcirculation (20). Arteriolar
vasodilation, and consequent reduction of peripheral vascular
resistance, is a primary compensatory response to ischemia
(51). Peripheral arterioles in CLI patients are relatively insensitive to vasodilator stimuli compared with those in control
subjects, thus demonstrating that arterioles in CLI patients are
maximally dilated (28). McEwan and Ledingham (55) proposed that compensatory vasodilation results in arteriolar dysfunction due to the chronic exposure of the arterioles to
vasorelaxing factors. They called this phenomenon “vasomotor
paralysis,” which has been identified as a contributing factor in
edema formation in CLI (51). In many CLI patients, elevation
of the feet results in capillary collapse and “pallor” of the distal
limb. Conversely, when the patients stand, blood drains unimpeded into the capillary beds of the lower limb. The lower
limbs become suffused with blood, observed as “rubor” (51).
Uncontrolled orthostatic-dependent increases in hydrostatic
pressure within the distal portion of the limb are likely to
contribute to the development of edema. Edema formation is a
paradoxical finding, because CLI, by definition, is a state of
hypopressure and hypoperfusion. Nonetheless, in ⬃70% of
patients with CLI, edema is confined to the distal portion of the
affected leg (44, 45). More than 90% of CLI patients undergo
angioplasty and/or vascular reconstruction within 1 yr of diagnosis (67). In a large number of CLI patients, bypass grafts that
are fully patent are not associated with normal blood perfusion
to the peripheries, with a significant number of these patients
forming postoperative edema. Consequently, many of these
patients must undergo amputation of the affected leg(s) (33, 62,
72). After these surgical interventions, postoperative leg edema
can develop as a consequence of the reintroduction of systemic
blood pressure to the distal portion of the limb. Edema formation in CLI further potentiates tissue metabolic insufficiency,
inasmuch as edema compresses the delicate capillaries and
impairs diffusion of nutrients to the surrounding tissues (55).
The orthostatic-dependent changes in lower limb blood perfusion described by Lowe (51) and the phenomenon of postoperative edema after revascularization demonstrate a circulatory
inadequacy to autoregulate blood hydrostatic pressure and
would favor the development of edema in CLI patients. The
ability to autoregulate blood flow to the capillary beds is
largely dependent on myogenic mechanisms of vascular tone,
The costs of publication of this article were defrayed in part by the payment
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Coats, Paul, and Roger Wadsworth. Marriage of resistance
and conduit arteries breeds critical limb ischemia. Am J Physiol
Heart Circ Physiol 288: H1044 –H1050, 2005; doi:10.1152/ajpheart.
00773.2004.—Atherosclerosis in a major leg artery leads to impaired
blood supply, which normally progresses to critical limb ischemia.
Atherosclerosis produces substantial alterations of structure and endothelial function in the large conduit arteries. Pressure unloading and
ischemia in the distal vasculature bring about alterations in microvascular function. Resistance arteries undergo significant wall thinning
and changes in their contractile regulation. Optimization of large
artery dimensions by the small arteries through flow-mediated vasodilation is impaired. Angiogenesis is stimulated, which can result in
the formation of major collateral feeder vessels in addition to small
nutritive blood vessels. However, angiogenesis can also contribute to
instability of atherosclerotic plaques, which ultimately leads to further
deterioration in blood supply. Surgical bypass grafting to restore
blood supply to the distal leg generates a sudden increase of pressure
in the weakened resistance vasculature, leading to uncontrolled
changes in capillary hydrostatic pressure, extravasation of fluid, and
tissue edema. This review aims to highlight the importance of the
resistance vasculature in critical limb ischemia and the interdependence of pathophysiological changes in the large conduit and small
resistance arteries. The major unresolved question is why the physiological mechanisms that regulate vascular structure and function
ultimately break down, leading to circulatory failure within the distal
limb.
ARTERY PATHOPHYSIOLOGY IN ISCHEMIC VASCULAR DISEASE
an intrinsic property of resistance arteries (56). Thus, despite
the disease process in CLI originating at the level of the large
communicating arteries, the subsequent downstream chronic
ischemia produces structural and functional adaptations within
the small resistance arteries. Paradoxically, rectification of the
large artery disease, the primary cause of the condition,
through surgical intervention is consequently compromised by
the secondary small artery disease.
PATHOPHYSIOLOGICAL CHANGES IN CONDUIT ARTERIES
AJP-Heart Circ Physiol • VOL
Flow-mediated vasodilation has been demonstrated in the
human femoral artery during reactive hyperemia. Reactive
hyperemia is caused by a downstream vasodilation and increased blood flow, which releases vasodilator factors from the
endothelium of the feeder artery, with consequent relaxation.
In healthy human subjects, the femoral artery remained dilated
for ⱖ3 min after the shear force on the femoral artery endothelium had returned to baseline (60). Additional mechanisms
for communication along the length of an artery include endothelial cell-to-cell communication (31). These studies demonstrate a powerful modulation of the distributing arteries by the
microvasculature; however, it is not clear how the endothelium
brings about long-lasting changes in artery structure.
ANGIOGENESIS IN LIMB ISCHEMIA
The vascular network has a remarkable degree of plasticity
and the capacity for significant restructuring through angiogenesis, arteriogenesis, and arterial remodeling. Angiogenesis
(capillary sprouting) and arteriogenesis (expansion of preexisting collaterals) are physiological responses to increased demand for blood supply and are stimulated by factors such as
tissue hypoxia and alterations in blood flow. Angiogenesis
involves the coordinated migration, proliferation, assembly,
and maturation of endothelial cells, smooth muscle cells, and
other cell types and is under the control of several growth
factors, of which the most extensively studied are vascular
endothelial growth factor (VEGF), fibroblast growth factor,
platelet-derived growth factor, and angiopoietin.
VEGF is produced by the vascular endothelium and other
cells of the artery wall and causes endothelial cell proliferation
and endothelial tube formation. The effects of VEGF and NO
are intertwined. Thus VEGF stimulates NO formation by
endothelial cells, and the angiogenic actions of VEGF appear
to be mediated by NO (90). Moreover, NO induces VEGF
mRNA and protein synthesis in cultured smooth muscle cells
(34). The improvement in limb blood flow and capillary
density induced by endothelial NO synthase gene administration was abolished by anti-VEGF antibody (61).
In a mouse model of leg ischemia (femoral artery ligation),
the development of new capillaries was impaired in atherosclerotic compared with control mice. Blood flow restoration was
also slower in the atherosclerotic animals and correlated with
capillary density. In the atherosclerotic mice, infiltration of T
cells, which were positive for VEGF, was reduced, and thus
VEGF was reduced in the ischemic limbs (24). Recovery of
blood flow after femoral artery ligation was also delayed in
another mouse model of hyperlipidemia compared with wildtype mice. Administration of hepatocyte growth factor restored
capillary density and blood flow to the level observed in mice
with normal lipid profiles but did not accelerate angiogenesis in
wild-type mice (57). Similar improvements in capillary density
and blood flow were found in a rat hindlimb ischemia model (79).
Angiogenesis can occur in various locations, resulting in
beneficial or detrimental consequences. Improved blood flow
may result from increased density of nutritive arteries in the
ischemic limb tissue or from formation of bypass channels that
divert blood around an obstruction (24, 59, 79). In contrast,
angiogenesis within atherosclerotic plaque tissue is considered
to be detrimental, because new vessels in this location are
highly susceptible to rupture, and intraplaque hemorrhage is
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Artery structure. Remodeling of artery structure in accordance with changing physiological demands has been extensively studied in animal models and has also been demonstrated in human leg arteries. However, almost two-thirds of
the population in late middle age has evidence of atherosclerotic disease of the femoral artery (49), and normal artery wall
structure cannot be maintained in plaque regions. In healthy
subjects, leg exercise increased the diameter and reduced
intima-media thickness of the femoral artery. The mechanism
probably involves increased blood flow through the femoral
artery, initiating vasodilation and outward remodeling of the
femoral artery wall (30). In contrast, areas of atherosclerotic
plaque show inward remodeling and intimal hypertrophy. In
patients with more advanced disease, exercise will be limited,
and the resulting loss of exercise-induced outward arterial
remodeling will exacerbate the deterioration in artery structure
caused by atherosclerotic disease.
Endothelium. Endothelial function is impaired in patients
with peripheral artery disease. In a study of patients with
identified significant disease affecting a major leg artery, flowmediated vasodilation in the brachial artery was substantially
reduced compared with the matched control group (9, 89).
Because endothelial responsiveness was impaired in a vascular
bed distant from the most severe atherosclerotic plaques, these
data are consistent with the concept of atherosclerosis as a
systemic disease with consequences that are widespread
throughout the vasculature. Endothelial dysfunction was found
to correlate with plasma concentrations of the inflammatory
markers C-reactive protein, fibrinogen, soluble intercellular
adhesion molecule-1, and soluble vascular cell adhesion molecule-1 (9, 10). These data demonstrate a significant degree of
inflammation in patients with leg ischemia. One mechanism
through which inflammation may contribute to endothelial
dysfunction is production of oxygen radicals that destroy nitric
oxide (NO) and have cytotoxic actions. Consistent with this
view, it has been found that administration of L-arginine to
hypercholesterolemic subjects improved flow-mediated vasodilation and normalized the plasma level of thiobarbituric
acid-reactive substances (a measure of oxidative stress) (43).
Shear forces acting on the endothelium increase expression
of NO synthase and superoxide dismutase, which, along with
other endothelial mediators, are important in the vasculoprotective effects of exercise. Exercise was found to improve
endothelium-dependent relaxation in middle-aged subjects, including hypercholesterolemic subjects who were treated with
lipid-lowering agents (87, 88). However, exercise training
produced less aortic wall stress in older than in younger
subjects (17, 18), and this may be one reason for deteriorating
endothelial function with increasing age.
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ARTERY PATHOPHYSIOLOGY IN ISCHEMIC VASCULAR DISEASE
PATHOPHYSIOLOGICAL CHANGES IN
RESISTANCE ARTERIES
Resistance arteries with an internal diameter of ⬃150 ␮m
contribute significantly to total peripheral resistance and basal
vascular tone (58). The fundamental function of resistancesized arteries is control of blood flow to the capillary beds,
which maintains an optimal pressure-flow relation, which in
turn is essential for gas and nutrient exchange from blood to
tissue. This is partly achieved by a putative pressure-sensing
mechanism, which stimulates a myogenic response in the
vascular smooth muscle (25, 56). The ability of a resistance
artery to withstand pressure-dependent distension is the sum of
two intrinsic components: active myogenic tone and passive
structural properties of the artery.
Pressure-dependent vascular wall stress and, to a lesser
extent, shear stress are recognized as the major determinants of
vascular wall structure (12, 46, 69). There have been few in
vitro studies on the effect of reducing environmental stimuli,
such as blood pressure and blood flow, on vascular structure
and function and certainly none in human subjects over an
extended period. Studies have demonstrated arteriolar structural and functional plasticity as a product of intraluminal
pressure and flow dynamics (26, 70). This is most evident in
animal models of hindlimb unloading, where the animal is
suspended by the tail for a period of days and blood volume is
unloaded from the hindlimb, inducing a cephalic fluid shift and
postural muscle unloading (26). These animals manifest many
of the adaptations that are found in CLI, including postural
muscle atrophy, diminished capacity to elevate vascular resistance in the skeletal muscle microvasculature within the limb,
uncontrolled orthostatic-dependent changes in limb volume,
and reduced aerobic muscle capacity (26). Studies of skeletal
muscle arterioles from these animals indicate that at least part
of the inability to control vascular resistance results from a
blunting of myogenic autoregulation (26). Significantly, the
microvascular effects of hindlimb unloading have also been
reported to be readily reversible after normal orientation, with
restoration of vascular structure and function, including pressure-dependent myogenic reactivity (52).
AJP-Heart Circ Physiol • VOL
Hypertension has long been associated with structural
changes in small resistance arteries characterized by hypertrophic or eutrophic inward remodeling (3–5, 37). There are,
however, only a few studies of the effects of low blood
pressure (hypotension) and low blood flow on resistance vascular structure (19, 20, 70). In these studies, reversal of the
hypertensive stimuli reversed hypertension-associated structural adaptations (12), low flow resulted in outward hypotrophic remodeling (69, 70), and low blood pressure resulted in a
reduced media-to-lumen ratio (21). The structural changes
observed in resistance arteries from patients with CLI, a
hypotensive state, are essentially the opposite of those observed in hypertension, thus reaffirming the association between blood pressure and vascular structure. Pressure-dependent mechanical forces are known to influence vascular structure. The mechanisms involved are unclear, but mechanical
forces have been shown to upregulate vascular smooth muscle
DNA synthesis and cell growth (69, 86). Moreover, many of
the structure adaptations to blood flow and pressure have been
observed to be endothelium dependent via the release of
endothelium-derived mitogens, such as angiotensin II and
endothelin, or the enhancement of endothelial cell adhesion
molecules and subsequent activation of mitogenic growth factors such as platelet-derived growth factor (48, 65, 72, 74).
These studies have focused on hypertension and/or intimal
hyperplasia; however, if these factors are upregulated as a
consequence of increased blood pressure-increased shear
stress, then it is plausible that they are downregulated in low
blood pressure-low shear stress, such as CLI. Vascular structure is closely correlated with function (58). Resistance artery
responses to agonist- and pressure-dependent (myogenic) stimuli are much greater in hypertensive than in normotensive
models (29, 35, 80).
CLI, a hypotensive-hypoperfusion state, is correlated with
morphological changes that are the opposite of those observed
in hypertension, i.e., decreased wall thickness, decreased crosssectional area, and decreased wall-to-lumen ratio compared
with controls (20). Furthermore, in CLI, the changes in vascular wall composition parallel changes in vascular wall mechanics. Specifically, incremental distensibility, wall stress, wall
strain, and tangential elastic moduli are altered, favoring increased compliance and reduced ability to withstand pressuredependent dilation. Clearly, the resistance in the distal portion
of a chronically ischemic limb has neither the structural nor the
functional properties of a resistance artery. Therefore, it is not
surprising that, after reintroduction of higher pressure, edema
forms in the affected part of the leg. These observations are
important, because they provide an explanation for postoperative edema development after the return of systemic perfusion
pressures following revascularization, which can result in graft
failure and poor wound healing, which in turn may accelerate
the requirement for amputation in CLI patients.
Endothelium. CLI is associated with hemostasis and microthrombosis within the capillaries plus edema, all of which have
been attributed to endothelial dysfunction (32). The vascular
endothelium has several key physiological functions, including
modulation of vascular tone, antithrombogenic barrier, and
control of vascular permeability. There have been no in-depth
studies on the effect of chronic ischemia on vascular endothelium of small resistance arteries. However, the effect of stroke
and ischemia-reperfusion injury on endothelial structure and
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one of the key factors leading to plaque deterioration and
instability (8, 41). VEGF is localized to these intraplaque
vessels (8, 41), and in a cholesterol-fed rabbit model, administration of recombinant VEGF increased atherosclerotic
plaque area (16). Thus it is possible that angiogenesis may
limit or, in contrast, promote the progression of CLI.
In patients with peripheral artery disease, elevated plasma
VEGF was reduced to normal on revascularization (54, 70),
suggesting that angiogenesis is stimulated during limb ischemia. Attempts have been made to administer VEGF by gene
therapy to patients with leg ischemia. In preliminary trials,
ankle blood pressure and collateral vessel formation were
improved (6, 71). However, in a randomized double-blind
study, no significant difference in walking time or ankle blood
pressure was found between VEGF gene-treated and control
groups (71). This negative clinical result compared with the
positive results in animal studies may indicate that the dose of
VEGF delivered in this particular trial was insufficient, that
VEGF needs to be augmented by other growth factors, or that
detrimental angiogenesis in plaque areas is a limiting factor.
ARTERY PATHOPHYSIOLOGY IN ISCHEMIC VASCULAR DISEASE
what appears to be preserved endothelial function may, in fact,
be compensatory. Further studies are required to elucidate this
point.
Ischemia is, in part, compensated by the release of EDRFs
(51), which results in arteriolar vasodilation, increased blood
flow, and cessation of ischemia. The constant activation of the
vasodilator compensation mechanism via release of the
EDRFs, factors known to inhibit protein synthesis, over a
prolonged period must have some effect on artery structure.
This may be advantageous in the early stages of CLI; however,
over time, this mechanism may have an indirect detrimental
effect on artery function because of the inhibition of protein
synthesis. This, combined with the reduction in blood flowand pressure-dependent stimuli that helps maintain arterial wall
structure, may explain the atrophic changes observed in the
arteries isolated from the ischemic vascular beds of patients
with CLI (21).
Oxygen radicals. The generation of phagocyte-derived oxygen free radicals, which is detrimental to vascular endothelial
function, is a key initiating step in the atherogenic process in
large arteries. However, there is no evidence for similar atherogenic processes in the small resistance arteries. There is growing evidence that reactive oxygen species (ROS), such as
hydrogen peroxide and superoxide, play an important role in
intracellular cell signaling (7, 42, 83). The NAD(P)H oxidase
system is a principal generator of intracellular ROS in vascular
smooth muscle cell signaling (38, 75). The capacity of vascular
smooth muscle NAD(P)H oxidase to generate ROS is much
lower than that of phagocytes, and generation of ROS appears
to be mainly intracellular (39). In fact, ROS via NAD(P)H
oxidase has been shown to modulate myogenic tone in resistance-sized arteries (63). These findings are important, inas-
Fig. 1. Postulated overview of physiological adaptations of the vasculature in critical limb ischemia.
AJP-Heart Circ Physiol • VOL
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function has been studied in the cerebral resistance vasculature
(1, 27, 52). In these studies, ischemia has been associated with
endothelial cell swelling, increased endothelial permeability,
and, subsequently, edema formation (1, 53). These changes
have been associated with an increase in release of VEGF (1,
72, 82). Moreover, after ischemia, the vascular endothelium in
the cerebral vasculature has been shown to take on a proinflammatory phenotype, resulting in increased expression of
adhesion molecules and release of numerous vasoactive and
proinflammatory mediators, including prostaglandins, leukotrienes, cytokines, and platelet-activating factor (50, 81). Similarly, microthrombosis, endothelial swelling, and edema have
been reported as being potential causes of microcirculatory
blood flow abnormalities in CLI (15, 22, 36).
Diabetes and hypertension have been associated with resistance artery endothelial dysfunction (48, 76). In CLI the
pathophysiological effects are thought to be a consequence of
a complex set of endothelium-dependent events that evoke an
inappropriate activation of microvascular-dependent flow and
deposition of microthrombi within the microvascular beds (32,
51). Central to the ischemia-dependent activation of microvascular-dependent flow is release of endothelium-derived relaxing factor (EDRF). However, in CLI, where diabetes and
hypertension are prevalent, there is likely a degree of endothelial trauma that may be responsible for increased free radical
production, inappropriate platelet activation, leukocyte adhesion, and, consequently, microthrombi formation. However,
our own studies have shown that the endothelium in resistance
arteries isolated from ischemic regions is intact and displays
vasodilator function comparable to that of control tissues (20).
This alone is a surprising observation, inasmuch as CLI patients are often diabetic and/or hypertensive; thus it may be that
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ARTERY PATHOPHYSIOLOGY IN ISCHEMIC VASCULAR DISEASE
much as they clearly show that ROS are not detrimental to
vascular function and do, in fact, play a crucial role in modulating fundamental physiological vascular performance,
namely, pressure-dependent myogenic tone.
9.
Perspectives
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
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CLI is a common manifestation of atherosclerosis, characterized by progressive deterioration of the limb circulation.
Studies of conduit and resistance arteries from patients with
CLI have shown marked physiological changes in advanced
disease. Studies in animal models have elucidated mechanisms
that maintain healthy structure and function of large and small
arteries and their interdependence. The two recognized compensatory mechanisms recruited in CLI are compensatory vasodilation and formation of a collateral circulation. These
mechanisms are presumably adequate in the initial stages of
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Patients with CLI will, wherever possible, undergo a surgical revascularization procedure such as a bypass graft. Limb
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