Regulation of Microvascular Function by ROS

ROS对微血管功能的调节

• 批准号: 7218283
• 负责人: CHRISTOPHER S WILCOX
• 金额: $ 47.4万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7218283
• 关键词: Accounting; Agonist; Angiotensin II; Antioxidants; Blood Vessels; Buffers; Calcium; Complication; Contracts; Cuprozinc Superoxide Dismutase; Development; Endothelin; Endothelin-1; Endothelium; Enzyme Activators; Enzymes; Equilibrium; Excretory function; Figs - dietary; Gene Silencing; Gene Targeting; Generations; Genes; Homeostasis; Hydrogen Peroxide; Hypertension; Individual; Infusion procedures; Injection of therapeutic agent; Intake; Intravenous; Kidney; Knock-out; Knockout Mice; Lead; Lipids; Mediating; Mediation; Mesentery; Metabolism; Modeling; Molecular; Multienzyme Complexes; Mus; NADP; NADPH Oxidase; Nitric Oxide; Oryctolagus cuniculus; Oxidases; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Pharmaceutical Preparations; Play; Principal Investigator; Process; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Protein Isoforms; Proteins; RNA Interference; Rate; Rattus; Reactive Oxygen Species; Regulation; Relaxation; Research Design; Research Personnel; Resistance; Rho-associated kinase; Role; Role playing therapy; Small Interfering RNA; Smooth Muscle Myocytes; Sodium Chloride; Source; Superoxide Dismutase; Superoxides; Testing; Thromboxane Receptor; Thromboxanes; Time; Transplantation; Tubular formation; Up-Regulation; Vascular resistance; Vasoconstrictor Agents; arteriole; base; cyclooxygenase 1; cyclooxygenase 2; design; enhancing factor; feeding; hemodynamics; human CYBA protein; in vivo; inhibitor/antagonist; intravital microscopy; kidney vascular structure; knockout gene; mouse model; peroxidation; prevent; programs; receptor; research study; response; rho; salt balance; vasoconstriction

Low rates of Angiotensin II (Ang II) infusion increase reactive oxygen species (ROS), upregulate key renal components of NADPH oxidase (p22phox, NOX-1) and downregulate EC-SOD. Antioxidant drugs implicate ROS in the development of hypertension, yet the specific roles of renal and systemic ROS in vasoconstriction, salt retention and the mediation by NADPH oxidase, or by reduced SOD-dependent defense in the kidney, are largely undefined. We will study BP homeostasis (telemetric BP), salt handling and sensitivity and microvascular mechanisms in mice (isolated, perfused renal afferent and mesenteric resistance vessels and in vivo intravital microscopy) to explore the roles of an endothelium-derived contracting factor (EDCF) and enhanced VSMC contractility in the microvessels. We will relate these functional studies to ROS, NO, and calcium activity in individual microdissected vessels and pre-glomerular vascular smooth muscle cells. Our primary strategy is the use of knockout models and small interference RNAs (siRNAs) directed at target genes delivered intrarenally to assess specifically renal mechanisms of hypertension. This will be extended with kidney cross-transplantation combined with a cre-lox strategy to knockout genes specifically in VSMC to establish, for the first time, the roles of the kidney and its afferent arterioles in mediating hypertension with ROS. Aim 1 will use the EC-SOD -/- mouse model of stable, sustained microvascular oxidative stress to test the hypothesis that oxidative stress releases endothelin, which acts on type A or B receptors to engage a cyclooxygenase-derived EDCF that activates adjacent VSMCs where contractility is enhanced by a Ca++ sensitizing pathway mediated by rho/rho kinase. Aim 2 will use EC-SOD -/- mice administered siRNA to IC-SOD delivered selectively to the kidney to test the hypothesis that IC-SOD is the major antioxidant defense in the kidney and that its renal deficiency promotes renal vasoconstriction, salt retention, and hypertension. Aim 3 will use normal mice with siRNA to p22phox delivered to the kidney or systemically to test the hypothesis that renal NADPH oxidase mediates increased afferent arteriolar contractility, RVR, salt retention and hypertension with Ang II. These projects are an integrated approach to dissect the roles of ROS in renal microvascular reactivity and salt handling that constitute renal mechanisms of hypertension.

低速率血管紧张素II（Ang II）输注增加活性氧（ROS），上调关键的肾脏 NADPH氧化酶（p22 phox，NOX-1）的活性，下调EC-SOD活性。抗氧化剂药物 活性氧在高血压的发展中的作用，但肾脏和全身活性氧在高血压的发展中的特殊作用， 血管收缩，盐潴留和NADPH氧化酶的介导，或减少SOD依赖性 肾脏的防御机制，在很大程度上是不确定的。我们将研究血压稳态（遥测血压），盐处理 和敏感性和微血管机制在小鼠（离体，灌注肾传入和肠系膜 阻力血管和体内活体显微镜），以探索内皮源性 血管收缩因子（EDCF）和增强微血管中VSMC的收缩性。我们将把这些 功能研究ROS，NO，和钙活性在个别微切割血管和肾小球前 血管平滑肌细胞我们的主要策略是使用敲除模型和小干扰 靶向靶基因的RNA（siRNA）经肾内递送，以评估特异性的肾脏机制， 高血压这将通过肾交叉移植结合cre-lox策略来扩展， 敲除VSMC中的特异性基因，首次建立肾脏及其传入神经的作用。 小动脉介导ROS高血压。目的1将使用稳定、持续的微血管氧化应激的EC-SOD -/-小鼠模型来测试氧化应激的假设 应激释放内皮素，内皮素作用于A型或B型受体以接合环加氧酶衍生的EDCF 激活邻近的VSMC，其中收缩性通过Ca++敏化途径增强， rho/rho激酶。目的2将使用EC-SOD -/-小鼠施用siRNA以将IC-SOD选择性地递送至 肾脏来测试假设，即IC-SOD是肾脏中的主要抗氧化防御，其肾脏 缺乏促进肾血管收缩、盐潴留和高血压。AIM 3将使用正常小鼠 将针对p22 phox的siRNA递送至肾脏或全身，以检验肾脏NADPH 氧化酶介导血管紧张素II增加的传入小动脉收缩力、RVR、盐潴留和高血压。 这些项目是一个综合的方法来剖析ROS在肾微血管反应性中的作用， 盐处理构成高血压的肾脏机制。