Vascular Reactivity: Gender and Hormonal Influence

描述（由申请人提供）：最近对性腺类固醇血管作用的理解激增，包括两种雌激素受体（ER）的鉴定以及基因组和非基因组机制。然而，主要的问题仍然是关于哪些受体和哪些机制对性腺激素的作用贡献最大。因此，我们将继续整合功能和生化方法，在体内使用慢性激素治疗来强调脑循环中的生理相关作用。主要假设是：雌激素和睾酮通过影响内皮机制改变脑血管功能。将从长期服用性腺类固醇的大鼠和小鼠身上分离出脑动脉。血管收缩力，内皮钙，平滑肌膜电位，血管活性因子合成蛋白及其释放将被量化。将测试四个特定的假设：1。雌激素，通过激活erα，增加内皮依赖性脑血管扩张。雌激素可能影响至少三种血管扩张剂：一氧化氮、前列环素和内皮源性超极化因子（EDHF）。我们将测试雌激素治疗是否会增加EDHF介导的血管舒张，调节雌激素作用的内皮因子之间是否存在显著的相互作用，雌激素治疗是否会增加内皮钙，以及雌激素对脑血管内皮功能的影响是否通过er α的基因组作用介导。2. 睾酮通过内皮依赖机制增加脑血管收缩。由于睾酮治疗增加脑血管收缩，我们将测试睾酮是否影响内皮血管收缩和/或血管舒张因子。3. 雌激素或睾酮会改变COX-2或iNOS的诱导。我们将监测iNOS和COX-2诱导，并确定性腺类固醇是否调节炎症反应。4. 孕激素会调节雌激素的作用。我们将评估慢性黄体酮治疗是否会改变雌激素对血管的作用。鉴于已知的心血管疾病发病率的性别差异以及激素替代疗法在很大一部分人群中的适用性，这项工作对于理解脑循环的生理控制以及改进激素治疗具有重要意义。

DESCRIPTION (provided by applicant): The recent explosion in understanding vascular effects of gonadal steroids includes identification of two types of estrogen receptor (ER) and both genomic and non-genomic mechanisms. Still, major questions remain concerning which receptors and which mechanisms contribute most to the actions of gonadal hormones. Therefore, we will continue to integrate both functional and biochemical approaches, using chronic hormone treatment in vivo to emphasize physiologically relevant effects in the cerebral circulation. The major hypothesis is: Estrogen and testosterone alter cerebrovascular function by influencing endothelial mechanisms. Cerebral arteries will be isolated from rats and mice chronically treated with gonadal steroids. Vascular contractility, endothelial calcium, smooth muscle membrane potential, synthetic proteins for vasoactive factors and their release will be quantified. Four specific hypotheses will be tested: 1. Estrogen, by activating ERalpha, increases endothelial-dependent cerebrovascular dilation. Estrogen may influence at least three vasodilators: NO, prostacyclin and endothelial derived hyperpolarizing factor (EDHF). We will test whether estrogen treatment increases vasodilation mediated by EDHF, whether there are significant interactions among endothelial factors that modulate estrogen effects, whether estrogen treatment increases endothelial calcium, and whether effects of estrogen on cerebrovascular endothelial function are mediated by genomic actions of ERalpha. 2. Testosterone increases cerebrovascular constriction through endothelial-dependent mechanisms. Since testosterone treatment increases cerebrovascular constriction, we will test whether testosterone affects endothelial vasoconstrictor and/or vasodilator factors. 3. Induction of COX-2 or iNOS will be altered by estrogen or testosterone. We will monitor iNOS and COX-2 induction and determine if gonadal steroids modulate inflammatory responses. 4. Progestins will modulate effects of estrogen. We will assess whether chronic progestin treatment alters vascular effects of estrogen. Given known sex differences in incidence of cardiovascular disease as well as the applicability of hormone replacement therapy to a large segment of the population, this work has tremendous significance for understanding physiological control of the cerebral circulation as well as improvement of hormonal therapy.