Mechanisms of Peripheral Microvascular Disease

周围微血管疾病的机制

• 批准号: 7008881
• 负责人: David W Stepp
• 金额: $ 33.86万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-15 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7008881
• 关键词: alpha adrenergic receptor; disease /disorder model; enzyme linked immunosorbent assay; hemodynamics; insulin sensitivity /resistance; laboratory rat; metabolic syndrome; microcirculation; muscle function; musculoskeletal circulation; obesity; peripheral blood vessel disorder; polymerase chain reaction; receptor expression; statistics /biometry; striated muscles; vasoconstriction; western blottings

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.

描述（由申请人提供）：美国人目前生活在肥胖和相关风险因素的流行之中，这种情况被称为代谢综合征X。外周血管疾病（PVD）是X综合征患者中最令人衰弱的痛苦之一，X综合征是肥胖、胰岛素抵抗、高血压和II型糖尿病的组合表现。导致PVD的因素仍然知之甚少。本申请的目的是使用X综合征的动物模型来鉴定可能易患PVD的骨骼肌微循环扰动的原因和机制。初步数据确定了骨骼肌微血管的2个主要缺陷：对肾上腺素能刺激的反应性增强和微血管重塑为更小、更硬的小动脉。本提案的目的1将检验以下假设：与X综合征相关的胰岛素抵抗是后肢循环中肾上腺素能过度收缩的根本原因，并且这种增强的机制是α-肾上腺素受体表达的增加。目的2将检验以下假设：在X综合征的生理和药理条件下，后肢血流受限，并且这种受限通过抑制α-肾上腺素能过度收缩而减轻。目的3将检验以下假设：X综合征中后肢微循环的重塑反映了由血管收缩增强引起的低流量，而不是压力升高，并且这种重塑是由MMP的激活和血管抑素的表达介导的。我们进一步假设运动可以通过长期增加骨骼肌的血流量来改善重塑。总之，这些实验将确定代谢综合征X模型中血管功能障碍的新机制，并可能有助于确定治疗外周血管疾病的新治疗靶点和策略。