Mechanisms of Peripheral Microvascular Disease

周围微血管疾病的机制

• 批准号: 6872681
• 负责人: David W Stepp
• 金额: $ 34.68万
• 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/6872681
• 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危险因素流行的环境中，这种情况被称为代谢 X 综合征。周围血管疾病 (PVD) 是 X 综合征患者最令人衰弱的疾病之一，该病是肥胖、胰岛素抵抗、高血压和 II 型糖尿病的综合表现。导致 PVD ​​的因素仍知之甚少。当前应用的目标是使用 X 综合征的动物模型来确定可能诱发 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两个主要缺陷：对α-肾上腺素能刺激的反应性增强以及微血管重塑为更小、更僵硬的小动脉。该提案的目标 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-肾上腺素能受体表达的增加。目标 2 将检验 X 综合征中后肢血流在生理和药理学条件下均受到限制的假设，并且通过抑制 α-肾上腺素能过度收缩性可以缓解这种限制。目标 3 将检验以下假设：X 综合征中后肢微循环的重塑反映了血管收缩增强导致的低流量，而不是压力升高，并且这种重塑是由 MMP 的激活和血管抑制素的表达介导的。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。总而言之，这些实验将确定代谢 X 综合征模型中血管功能障碍的新机制，并可能有助于确定治疗周围血管疾病的新治疗靶点和策略。