Hypertension, Angiotensin and Neurovascular Regulation

高血压、血管紧张素和神经血管调节

• 批准号: 7439027
• 负责人: Costantino Iadecola
• 金额: $ 33.39万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7439027
• 关键词: Affect; Angiotensin II; Blood Vessels; Blood flow; Brain; Cerebrovascular Circulation; Cerebrum; Core-Binding Factor; Coupling; Development; Endothelium; Enzymes; Functional disorder; Goals; Hypertension; Maintenance; Mediating; Mus; NAD(P)H oxidase; Neuraxis; Nitric Oxide; Oxidative Stress; Production; Protein Overexpression; Reactive Oxygen Species; Regulation; Renin-Angiotensin System; Role; Somatosensory Cortex; Source; Structure; Testing; Transgenic Mice; Vasodilator Agents; Vibrissae; angiotensin hypertension; cerebrovascular; insight; neural model; pressure; relating to nervous system; research study; response; superoxide dismutase 1; Affect; Angiotensin II; Blood Vessels; Blood flow; Brain; Cerebrovascular Circulation; Cerebrum; Core-Binding Factor; Coupling; Development; Endothelium; Enzymes; Functional disorder; Goals; Hypertension; Maintenance; Mediating; Mus; NAD(P)H oxidase; Neuraxis; Nitric Oxide; Oxidative Stress; Production; Protein Overexpression; Reactive Oxygen Species; Regulation; Renin-Angiotensin System; Role; Somatosensory Cortex; Source; Structure; Testing; Transgenic Mice; Vasodilator Agents; Vibrissae; angiotensin hypertension; cerebrovascular; insight; neural model; pressure; relating to nervous system; research study; response; superoxide dismutase 1

Imbalance within central autonomic networks may contribute to the development or maintenance of hypertension. Hypertension, in turn, exerts deleterious effects on the structure and function of the central nervous system, the cerebral circulation being a major target of these actions. The long-term goals of this project are: (a) to identify the mechanisms by which hypertension alters the regulation of the cerebral circulation during neural activity, and (b) to define how these alterations affect the structure and function of the brain. Project 1 will begin by testing the hypothesis that AngII impairs the mechanisms responsible for the increase in CBF induced by neural activation. In particular, the proposed studies will determine whether Ang II exerts this effect by acting on cerebral blood vessels and by interfering with the vascular mechanisms through which neural activity increases blood flow. The following specific hypotheses will be tested: (1) Ang II alters the "coupling" between cerebral blood flow and neural activity, (2) this effect is mediated by Ang II-induced production of reactive oxygen species in cerebral blood vessels and nitric oxide inactivation, and (3) NAD(P)H oxidase is a major source of the vascular reactive oxygen species contributing to the dysfunction. Studies will be conducted in mice in which arterial pressure is elevated by administration of Ang II. The increase in cerebral blood flow produced in the somatosensory cortex by whisker stimulation will serve as a model of neural activation. Cerebrovascular responses to endothelium-dependent and independent vasodilators, and cerebrovascular production of reactive oxygen species will be studied. The role of radicals will be examined using mice overexpressing superoxide dismutase-1. Mice lacking specific NAD(P)H oxidase subunits will be used to determine whether this enzyme is the source of oxidative stress. Transgenic mice overexpressing components of the renin-angiotensin system will also be used in some experiments. The results of these studies will enhance our understanding of the effects of hypertension on the brain and may provide insights into new treatment strategies aimed at counteracting these detrimental actions.

中央自主网络中的不平衡可能有助于高血压的发展或维持。高血压反过来对中枢神经系统的结构和功能产生有害影响，大脑循环是这些动作的主要目标。该项目的长期目标是：（a）确定高血压在神经活动期间改变大脑循环的机制，以及（b）定义这些改变如何影响大脑的结构和功能。项目1将首先检验以下假设：Angii损害了导致神经激活引起的CBF增加的机制。特别是，拟议的研究将确定ANG II是否通过对脑血管作用并通过干扰血管机制来发挥这种作用 神经活动会增加血液流动。将测试以下特定的假设：（1）ANG II改变了大脑血流和神经活动之间的“耦合”，（2）该作用是由Ang II诱导的脑血管中活性氧的产生和氮氧化物失活的活性剂和（3）NAD（3）NAD（P）Hoxidase的主要反应性的氧化物的作用来介导的。将在通过ANG II给药升高动脉压升高的小鼠中进行研究。晶须刺激在体感皮层中产生的脑血流的增加将作为神经激活的模型。对内皮依赖和独立的脑血管反应 将研究血管扩张剂和活性氧的脑血管产生。将使用过表达超氧化物歧化酶1的小鼠检查自由基的作用。缺乏特异性NAD（P）H氧化酶亚基的小鼠将用于确定该酶是否是氧化应激的来源。肾素 - 血管紧张素系统过表达的转基因小鼠也将用于某些实验。这些研究的结果将增强我们对高血压对大脑的影响的理解，并可能提供对旨在抵消这些有害行为的新治疗策略的见解。