The Effect of Aldosterone on Cerebral Blood Vessels

描述（由申请人提供）：有证据表明醛固酮参与人类原发性高血压的病理生理。醛固酮拮抗剂螺内酯可减少脑卒中易发自发性高血压大鼠（SHRSP）的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SHRSP脑血管管腔直径变小、壁变厚的原因，这可能加剧缺血造成的损伤。醛固酮已被证明可以增加EGFR受体（EGFR）的磷酸化和激活，并且在SHRSP的脑血管中EGFR mRNA升高，而螺内酯则会降低EGFR mRNA。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，并减小血管管腔直径：1)醛固酮激活经典的矿物皮质激素受体，增加EGFR的表达；2)醛固酮与小泡中的矿皮质激素受体结合，引起EGFR磷酸化的快速增加。体内和体外技术将用于测试特定的目标。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减小管腔直径独立于血压变化的假设。Aim 2将验证醛固酮通过矿化皮质激素受体增加EGFR表达的假设，Aim 3将验证醛固酮通过小泡依赖机制直接增强血管平滑肌细胞EGFR激活的假设。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，而且作为一种信号分子增强EGFR激活。

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.