The Impact of Outward Remodeling on Vasodilation in Skeletal Muscle Resistance Arteries

Abstract

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...

Vascular Reactivity in Newly-Formed and Mature Arterialized Collateral Capillaries

“…PEC baseline diameters were not collected at day zero, so parallels cannot be drawn at that time point. (13,26). PECs were impaired at day seven, but seem to continue the trend at day 21.…”

“…Because they do not typically dilate or constrict, capillaries may not normally conduct these signals so that, even when the capillaries have arterialized, they may not yet have the capacity to communicate the vasodilation signal stimuli at day seven (17). Although the impaired vasoconstriction is likely due to reduced smooth muscle cell function, it may also be explained by a lack of innervation of the arterialized capillaries, which could limit contractile abilities (26,69).…”

“…While these PECs differ from arterialized collateral capillaries in their anatomical position and remodeling methods, they can provide insight into the physiology of ACCs, without the influence of genetic differences between Balb/C mice and other strains with pre-existing collaterals (26,27). Smooth muscle cells (SMCs) surround PECs prior to arterial occlusion, allowing for arteriogenesis, while the collateral capillaries lack SMCs until they arterialize.…”

“…Arteriogenesis involves vessel enlargement in response to changes in shear stress, for example, when blood supply is redirected as a result of an occlusion (26). When preexisting collateral vessels (PECs) are present, blood flow will follow the path of least resistance and travel through the existing collateral network, around the occlusion (Figure 13).…”

“…Seven days following spinotrapezius feed artery ligation, the arterialized collateral capillaries that have formed do not vasodilate in response to muscle contraction (13). This inability to dilate is likely due to the arrangement and immaturity of smooth muscle cells (26,42). Smooth muscle is not typically present around capillaries, so it is possible that the cells require more than seven days to fully develop and orient themselves as the cells are either recruited from upstream arterioles or differentiate from existing perivascular cells (25,48,68).…”