DESCRIPTION (provided by applicant): Americans currently live in an epidemic of obesity and associated risk factors, a condition referred to as the metabolic Syndrome X. Peripheral Vascular Disease (PVD) is 1 of the most debilitating afflictions in patients with Syndrome X, which is the combined presentation of obesity, insulin resistance, hypertension and Type II diabetes. The factors that lead to PVD remain poorly understood. The goal of the current application is to use an animal model of Syndrome X to identify the causes and mechanisms of perturbations in the skeletal muscle microcirculation that may predispose to PVD. Preliminary data identify 2 major defects in skeletal muscle microvessels: An augmented reactivity to a-adrenergic stimulation and a microvascular remodeling to smaller, stiffer arterioles. Aim 1 of this proposal will test the hypothesis that the insulin resistance associated with Syndrome X is the underlying cause of adrenergic hypercontractility in the hindlimb circulation and that the mechanism of this augmentation is an increase in a-adrenoceptor expression. Aim 2 will test the hypothesis that hindlimb blood flow is limited under both physiologic and pharmacologic conditions in Syndrome X and this limitation is alleviated by inhibition of a-adrenergic hypercontractility. Aim 3 will test the hypothesis that remodeling of the hindlimb microcirculation in Syndrome X reflects low flow brought on by augmented vasoconstriction, not elevated pressure and that this remodeling is mediated by the activation of MMPs and expression of angiostatins. We further hypothesize that exercise can improve remodeling by chronically increasing blood flow to skeletal muscle. Taken together, these experiments will identify novel mechanisms of vascular dysfunction in a model of the metabolic Syndrome X and may help identify new therapeutic targets and strategies for treatment of peripheral vascular disease.
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