The Impacts of Arterial Occlusion, Sex, and Exercise on Arteriogenesis and Functional Vasodilation

The most frequent clinical presentation of peripheral arterial occlusive disease (PAOD) is intermittent claudication, which may be caused by impaired vasodilation. Patients demonstrate both local and systemic impairments in vasodilation, but as the collateral circulation is the primary site of resistance to the ischemic zone, impaired collateral vasodilation would have the greatest potential to induce claudication. Collateral function following arterial occlusion is not well defined, but immature collaterals may demonstrate impaired vasodilation in animal models, although this is potentially improved with exercise training. Furthermore, as females exhibit poorer physical function with ischemia and less improvement with therapeutic exercise, there appears to be a sexually dimorphic response to PAOD, warranting a comparison in collateral vasodilation between sexes. In this study, the femoral artery was ligated to induce chronic ischemia in sedentary and exercise-trained mice, and at 7 or 28 days post-surgery, the diameter of the gracilis collateral arteriole was measured at rest and after gracilis muscle contraction using intravital microscopy. No major sex differences were observed in any group. At day 7, both the resting and dilated diameters were increased, while vascular reactivity was minimal. By day 28, resting diameter decreased while maximal diameter was unchanged, causing an increase in functional vasodilation. Exercise training also improved vasodilation by decreasing collateral resting diameter. These results are consistent with reported trends in endothelium-dependent and smooth muscle-dependent vasodilation, which are impaired in immature vessels and improved with maturation and exercise, but the significance of the observed variations in resting diameter remains unclear. Large resting diameters at day 7 could be due to a loss of sympathetic tone or the proliferative and non-contractile state of smooth muscle cells, while decreased resting diameters at day 28 could indicate that a smooth muscle contractile phenotype has been restored, or that the gracilis collateral is no longer the primary collateral. However, the further research is required to determine the functional relevance of collateral resting diameter and its importance in the ischemic limb circulation