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The Effect of Aldosterone on Cerebral Blood Vessels

醛固酮对脑血管的影响

基本信息

批准号：
7530613
负责人：
ANNE M. DORRANCE
金额：
$ 21.32万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-05-01 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7530613
关键词：
Acetates Adrenalectomy Aldosterone Binding Blood Blood Pressure Blood Vessels Caliber Caveolae Cerebral Ischemia Cerebrovascular Disorders Cerebrum Chronic Data Deoxycorticosterone EGF gene Epidermal Growth Factor Epidermal Growth Factor Receptor Essential Hypertension Experimental Models Functional disorder Genetic Transcription Growth Factor Human Hypertension Hypotension In Vitro Inbred SHR Rats Inbred WF Rats Inbred WKY Rats Infarction Ischemia Mediating Membrane Messenger RNA Mineralocorticoid Receptor Mineralocorticoids Movement Muscle Pathogenesis Pathology Phosphorylation Rattus Receptor Activation Research Personnel Risk Role Scheme Signaling Molecule Smooth Muscle Myocytes Spironolactone Stroke Techniques Testing Thick Thinking Translations Wistar Rats caveolin 1 in vivo kidney cell mRNA Expression novel pressure programs receptor receptor density receptor expression size vascular smooth muscle cell proliferation

项目摘要

DESCRIPTION (provided by applicant): There is evidence that aldosterone is involved in the pathophysiology of human essential hypertension. Aldosterone antagonism with spironolactone reduces ischemic cerebral infarct size without lowering blood pressure in stroke prone spontaneously hypertensive rats (SHRSP). This finding is important because the mechanism by which hypertension increases the risk of cerebral ischemia is unknown. An increased responsiveness of vascular smooth muscle cells to epidermal growth factor (EGF) may be responsible for the smaller lumen diameter and thicker walls seen in the cerebral blood vessels of SHRSP, and this may exacerbate the damage caused by ischemia. Aldosterone has been shown to increase EGF receptor (EGFR) phosphorylation and activation, and EGFR mRNA increased in the cerebral blood vessels of SHRSP, which is decreased by spironolactone. We hypothesize that aldosterone increases cerebral infarct size and cerebral blood vessel wall thickness, and reduces vessel lumen diameter by two independent mechanisms: 1) aldosterone activates the classical mineralocorticoid receptors to increase EGFR expression; and 2) aldosterone binds to the mineralocorticoid receptors in the caveolae to elicit a rapid increase in EGFR phosphorylation. In vivo and in vitro techniques will be used to test the specific aims. Aim 1 will test the hypothesis that aldosterone increases ischemic cerebral infarct size and cerebral blood vessel wall thickness and reduces lumen diameter independently of changes in blood pressure. Aim 2 will test the hypothesis that aldosterone increases the expression of the EGFR through the mineralocorticoid receptors, and Aim 3 will test the hypothesis that aldosterone directly enhances EGFR activation in vascular smooth muscle cells via a caveolae dependent mechanism. These studies will elucidate a novel role for aldosterone in the pathogenesis of cerebrovascular disease, they will show that aldosterone not only increases EGFR density but also acts as a signaling molecule to enhance EGFR activation.

描述（申请人提供）：有证据表明醛固酮参与人类原发性高血压的病理生理学。安体舒通拮抗醛固酮减少易卒中自发性高血压大鼠（SHRSP）缺血性脑梗死面积而不降低血压。这一发现很重要，因为高血压增加脑缺血风险的机制尚不清楚。血管平滑肌细胞对表皮生长因子（EGF）的反应性增加可能是导致SHRSP脑血管管腔直径变小和管壁变厚的原因，这可能加剧缺血引起的损伤。醛固酮可增加SHRSP脑血管中表皮生长因子受体（EGFR）的磷酸化和激活，并增加EGFR mRNA的表达，而螺内酯可降低EGFR mRNA的表达。我们假设醛固酮通过两种独立的机制增加脑梗死面积和脑血管壁厚度，并减少血管腔直径：1）醛固酮激活经典的盐皮质激素受体，增加EGFR表达;和2）醛固酮与小窝中的盐皮质激素受体结合，引起EGFR磷酸化的快速增加。将使用体内和体外技术来测试特定目标。目的1将检验醛固酮增加缺血性脑梗死面积和脑血管壁厚度，并独立于血压变化而减小管腔直径的假设。目的2将检验醛固酮通过盐皮质激素受体增加EGFR表达的假设，目的3将检验醛固酮通过小窝依赖性机制直接增强血管平滑肌细胞中EGFR活化的假设。这些研究将阐明醛固酮在脑血管疾病发病机制中的新作用，它们将表明醛固酮不仅增加EGFR密度，而且作为信号分子增强EGFR活化。