The Impact of Outward Remodeling on Vasodilation in Skeletal Muscle Resistance Arteries Ryan GallagherPeripheral arterial occlusive disease (PAOD) is an ischemic disease characterized by narrowing of the peripheral arteries due to the accumulation of atherosclerotic plaque in the inner lining of the vessels, which disrupts blood flow to downstream tissues. Blood can be redirected into collateral vessels, natural bypasses around arterial occlusions, causing shear-induced outward remodeling of the vessels. The enlarged vessels facilitate transfer of increased blood flow to downstream tissues. The remodeling process, however, may impair vasodilation, which in turn may cause or contribute to intermittent claudication-transient pain brought on by locomotion. To stimulate the growth of collateral arteries, the femoral arteries of young, otherwise healthy mice were ligated distally to the profunda femoris, the stem to the gracilis collateral circuit. The diameter of the profunda femoris artery was measured at rest and following gracilis muscle contraction 7 and 28 days post-surgery using intravital microscopy. Enlarged resting diameter, consistent with collateral enlargement, and impaired vasodilation was observed at day 7, but not at day 28. To determine if impaired functional vasodilation is due to impaired endothelial-or smooth muscle-dependent responses during outward remodeling, cell-dependent vasodilators were applied to the hindlimb. Endothelial-and smooth muscle-dependent vasodilation was significantly impaired 7 days post-ligation, but not 28 days after. This data supports the hypothesis that smooth muscle dysfunction causes impaired functional vasodilation in the early stages of collateral enlargement. The most common symptom of PAOD is intermittent claudication, or transient limb pain associated with exercise that is relieved by rest, which affects 10% to 35% of patients [1]. Evaluating the distance a patient can walk until experiencing pain is the gold-standard method of quantifying the severity of intermittent claudication. Intermittent claudication is associated with a 2-to 4-fold increased risk of mortality, mainly from cardiovascular disease [6,7]. Forty to fifty percent of patients experience critical limb ischemia, a more severe form of PAOD in which leg pain does not correlate with exertion and is not relieved by rest due to severe blockage of vessels [6]. The etiology of PAOD is similar to other ischemic diseases, such as coronary heart disease, and involves atherogenesis induced by endothelial injury and inflammation MCP-1, which stimulates monocyte recruitment, induced collateral growth, but is unsuitable as a therapeutic as it is increases atherosclerotic plaque formation.Transforming growth factor beta-1 (TGFβ-1), a monocyte chemoattractant, is a promising therapeutic as it is both pro-arteriogenic and atheroprotective. In order for pro-13 arteriogenic therapies to be effective, the enlarged vessels need to maintain vasoreactivity to properly match tissue nutrient demand. During ar...
