Abstract
Stimulating collateral arteriogenesis is an attractive therapeutic target for peripheral artery disease (PAD). However, the potency of arteriogenesis-stimulation in animal models has not been matched with efficacy in clinical trials. This may be because the presence of enlarged collaterals is not sufficient to relieve symptoms of PAD, suggesting that collateral function is also important. Specifically, collaterals are the primary site of vascular resistance following arterial occlusion, and impaired collateral vasodilation could impact downstream tissue perfusion and limb function. Therefore, we evaluated the effects of arteriogenesis on collateral vascular reactivity. Following femoral artery ligation in the mouse hindlimb, collateral functional vasodilation was impaired at day 7 (17 ± 3 vs. 60 ± 8%) but restored by day 28. This impairment was due to a high resting diameter (73 ± 4 μm at rest vs. 84 ± 3 μm dilated), which does not appear to be a beneficial effect of arteriogenesis because increasing tissue metabolic demand through voluntary exercise decreased resting diameter and restored vascular reactivity at day 7. The high diameter in sedentary animals was not due to sustained NO-dependent vasodilation or defective myogenic constriction, as there were no differences between the enlarged and native collaterals in response to eNOS inhibition with L-NAME or L-type calcium channel inhibition with nifedipine, respectively. Surprisingly, in the context of reduced vascular tone, vasoconstriction in response to the α-adrenergic agonist norepinephrine was enhanced in the enlarged collateral (−62 ± 2 vs. −37 ± 2%) while vasodilation in response to the α-adrenergic antagonist prazosin was reduced (6 ± 4% vs. 22 ± 16%), indicating a lack of α-adrenergic receptor activation by endogenous norepinephrine and suggesting a denervation of the neuroeffector junction. Staining for tyrosine hydroxylase demonstrated sympathetic denervation, with neurons occupying less area and located further from the enlarged collateral at day 7. Inversely, MMP2 presence surrounding the enlarged collateral was greater at day 7, suggesting that denervation may be related to extracellular matrix degradation during arteriogenesis. Further investigation on vascular wall maturation and the functionality of enlarged collaterals holds promise for identifying novel therapeutic targets to enhance arteriogenesis in patients with PAD.
Highlights
Peripheral artery disease (PAD) affects ∼8.5 million people in the United States and most frequently manifests as intermittent claudication, or pain while walking [1, 2]
Resting diameter in the enlarged collateral (73 ± 4 vs. 36 ± 3 μm in the native collateral) was very close to the maximum diameter. This indicates that arteriogenesis reduced vascular reactivity, i.e., the difference between resting and dilated diameters, with a percent increase in diameter of only 17 ± 3% in the enlarged collateral vs. 60 ± 8% in the native collateral (Figure 1E)
Patients with severe cases of PAD have the prognosis of a 20% 5-year survival rate, which is on par with colorectal and pancreatic cancer [7]
Summary
Peripheral artery disease (PAD) affects ∼8.5 million people in the United States and most frequently manifests as intermittent claudication, or pain while walking [1, 2]. Enlargement of natural bypass collaterals through arteriogenesis generally improves patient prognosis with coronary ischemic disease [8,9,10], and the presence of collaterals is associated with improved walking performance in patients with PAD [11] These observations highlight the stimulation of collateral arteriogenesis as an attractive therapeutic target. Despite success in animal models [12,13,14] and unrandomized or unblinded clinical trials [15], delivering growth factors involved in arteriogenesis or transplanting bone-marrow derived cells have failed to enhance collateral arteriogenesis or improve functional outcomes in numerous double-blinded, placebo controlled, randomized clinical trials [15,16,17] This failure, coupled with the observation that collaterals are not always protective, suggests that the benefit of collaterals may depend on more than their mere presence. Larger and more numerous collaterals can be associated with reduced limb perfusion and greater prevalence of symptomatic PAD [18], and half of patients with enlarged coronary collaterals still experience ischemic pain during physical activity [19, 20]
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