Chronic ischemia does not impair skeletal muscle vasodilation capacity in outwardly remodeled collaterals
Matthew Yocum and Trevor Cardinal
California Polytechnic State University
Program No. 948.20
Abstract No. 5954
arteriogenic surgery involved the resection of the femoral artery from proxi-
Results
Discussion
mal to the muscular branch artery to mid-way between the knee and the heel
As expected arteriogenesis occurred in the muscular branch artery of the femoral
Functional hyperemia following collateral enlargemtent was not im-
(saphenous branch point) (Figure 2). The same vascular endpoints were ana-
artery ligation model, as the resting diameter increased by 17.4% (Figure 5A). How-
paired. This implies that in large arteries with modest outward remodel-
lyzed 2 weeks post surgery.
ever, vasodilatory ability of the musc. branch artery was not attenuated in this model
ing (17%), such as the muscular branch, elevated shear-wall-stress does
rial narrowing at various vascular sites in the limbs (and likely elsewhere), re-
as hypothesized (Figure 5B). In contrast, outward remodeling of the muscular branch
not induce endothelial dysfunction; more specifically by day 14 the
sulting in insufficient blood delivery (ischemia) to afflicted tissues. Ischemia is
artery did not occur in the resection model (Figure 6A). Additionally functional hy-
smooth muscle cell contractile phenotype may be sufficiently expressed
a fundamentally inherent complication and the predominant cause of the
peremia was not abrogated (Figure 6B).
for normal vasodilatory response. Under conditions where neutral remod-
Introduction
Peripheral Artery disease (PAD), an ischemic/atherosclerotic disorder of the extremities, is prevalent in 10-25% of patients over the age of 55, affecting 8 million people in the United States [1, 2]. Etiologically, atherosclerosis causes arte-
disease’s deleterious symptoms. Normal revascularization (blood flow recov-
eling occurred (resection), arterial vasodilation was also not inhibited.
ery) processes include angiogenesis (sprouting of capillaries) and outward re-
However, following femoral artery resection the muscular branch artery
modeling (collateral enlargement). Animal ischemia models have been utilized
was refractory to regaining resting vascular tone. After applying an elec-
to examine these recovery mechanisms and have led to the advent of various
trical stimulus the artery required 30-60 minutes to reacquire its resting
vascular growth promoting therapies still being tested for efficacy in PAD. Un-
diameter. This was large when compared to the 4-6 minutes that were re-
fortunately, even when revascularization is successful and normal blood flow is
quired of the alternate surgical models. Upon further reflection blood
flow through the muscular branch in the resection model was particularly
regained, adequate vascular function (vasodilation and vasoconstriction) is attenuated following chronic ischemia [3]. This vascular impairment is likely in-
low and turbulent (Figure 7). This low/turbulent blood flow may have
Figure 2. A diagram of the femoral artery resection model for hindlimb ischemia.
fluenced by a phenotypic shift in smooth muscle cells from contractile to syn-
contributed to this qualitatively observed vascular dysfunction and should
thetic activity. As proper vaso-active function is important for patient prognosis,
warrant further investigation.
we used a mouse model of ischemia to examine whether collateral expansion
promoting conditions caused vascular dysfunction.
Methods
To tease apart the potential physiological conditions that would induce blood
Figure 5. A bar graph comparing the muscular branch artery diameter (A) and vasodilatory ability (% increase) (B) in the li-
flow control impairment we utilized two surgical models of mouse hindlimb
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post surgery). SDF images of muscular branch artery changes in ligated mice (C).
ischemia, one resulting in arteriogenic (high shear stress, normoxia, modest inflammation) and another in non-arteriogenic (decreased blood flow and more
severe hypoxia and inflammation) tissue environment. The arteriogenic surgical
model involved the ligation of the superficial femoral artery distal to the deep
femoral artery branch point (Figure 1). Changes in the diameter of the muscular
branch artery were evaluated using SDF imaging two weeks post surgery at rest
Figure 3. The SDF imaging intravital microscope (1) was utilized to evaluate the muscular branch arte-
and following gracilis muscle stimulation (functional hyperemia). The non-
rial diameter at rest and following gracilis stimulation (negative electrode (2) and positive electrode (3)).
Figure 7. This diagram indicates how blood flow in the muscular branch artery becomes turbulent following
femoral artery resection. In the middle is an SDF image, which indicates flow turbulence through contrast visualized by cloudiness in the artery. Both the cauterized end of the muscular branch and the high resistance of
small arteries connected to the muscular branch (recall that resistance is inversely related to the radius to the
power of four) promote turbulent flow.
References
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2. He, Y., et al., Critical function of Bmx/Etk in ischemia-mediated arteriogenesis and angiogenesis. J Clin Invest, 2006. 116(9): p. 2344-55.
Figure 6. A bar graph comparing the muscular branch artery diameter (A) and vasodilatory ability (% increase) (B) in the re
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post surgery). SDF images of muscular branch artery changes in resected mice (C).
Figure 1. Diagram of the femoral artery ligation model. The red arrows show blood flow divergence following
the surgery.
Figure 4. The muscular branch artery (3) was imaged following contraction of the gracilis muscles
(rectangular box) induced by obturator nerve (2) stimulation with a negative electrode (1).
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