Mechanisms of Peripheral Microvascular Disease

周围微血管疾病的机制

• 批准号: 7337066
• 负责人: David W Stepp
• 金额: $ 30.51万
• 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 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7337066
• 关键词: Adrenergic Agents; Adrenergic Receptor; American; Angiostatins; Animal Model; Blood Circulation; Blood Vessels; Blood flow; Condition; Data; Defect; Diabetic Angiopathies; Epidemic; Etiology; Exercise; Functional disorder; Goals; Hindlimb; Hypertension; Insulin Resistance; Lead; Life; Matrix Metalloproteinases; Mediating; Metabolic Syndrome X; Microcirculation; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Obesity; Patients; Peripheral; Peripheral Vascular Diseases; Physiological; Risk Factors; Skeletal Muscle; Syndrome; Testing; adrenergic; arteriole; improved; insight; novel; novel therapeutics; pressure; research study; therapeutic target; vasoconstriction

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(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综合征患者最令人衰弱的疾病之一，它是肥胖、胰岛素抵抗、高血压和II型糖尿病的综合表现。导致PVD的因素仍然知之甚少。目前应用的目标是使用X综合征的动物模型来确定可能易患PVD的骨骼肌微循环障碍的原因和机制。初步数据表明，骨骼肌微血管有两个主要缺陷：对α-肾上腺素能刺激的反应性增强，以及微血管重构为更小、更僵硬的小动脉。这项建议的目的1将检验一种假设，即与X综合征相关的胰岛素抵抗是后肢循环肾上腺素能高收缩的根本原因，并且这种增强的机制是α-肾上腺素能受体表达的增加。目的2将验证以下假设：在生理和药物条件下，X综合征的后肢血流都是受限的，这种限制可以通过抑制α-肾上腺素能高收缩来缓解。目的3将验证一种假说，即X综合征后肢微循环的重塑反映了血管收缩增强而不是压力升高导致的低血流，并且这种重塑是由MMPs的激活和血管抑素的表达所介导的。我们进一步假设，运动可以通过慢性增加流向骨骼肌的血流量来改善重构。综上所述，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周围血管疾病的新治疗目标和策略。

项目成果

Insulin resistance impairs endothelial function but not adrenergic reactivity or vascular structure in fructose-fed rats.

胰岛素抵抗会损害果糖喂养大鼠的内皮功能，但不会损害肾上腺素能反应性或血管结构。

• DOI: 10.1080/10739680902832795
• 发表时间: 2009
• 期刊: Microcirculation (New York, N.Y. : 1994)
• 作者: Romanko,OlgaP;Ali,MIrfan;Mintz,JamesD;Stepp,DavidW
• 通讯作者: Stepp,DavidW

Preventing increased blood pressure in the obese Zucker rat improves severity of stroke.

预防肥胖 Zucker 大鼠血压升高可改善中风的严重程度。

• DOI: 10.1152/ajpheart.01111.2009
• 发表时间: 2010
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Osmond,JessicaM;Mintz,JamesD;Stepp,DavidW
• 通讯作者: Stepp,DavidW

Obesity increases blood pressure, cerebral vascular remodeling, and severity of stroke in the Zucker rat.

• DOI: 10.1161/hypertensionaha.108.124149
• 发表时间: 2009-02
• 期刊: Hypertension (Dallas, Tex. : 1979)
• 作者: Osmond JM;Mintz JD;Dalton B;Stepp DW
• 通讯作者: Stepp DW

Influence of obesity and metabolic dysfunction on the endothelial control in the coronary circulation.

• DOI: 10.1016/j.yjmcc.2011.08.018
• 发表时间: 2012-04
• 期刊: Journal of molecular and cellular cardiology
• 影响因子: 5
• 作者: Belin de Chantemele EJ;Stepp DW
• 通讯作者: Stepp DW

Protein tyrosine phosphatase 1B, a major regulator of leptin-mediated control of cardiovascular function.

• DOI: 10.1161/circulationaha.109.853077
• 发表时间: 2009-09-01
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Belin de Chantemèle EJ;Muta K;Mintz J;Tremblay ML;Marrero MB;Fulton DJ;Stepp DW
• 通讯作者: Stepp DW