Neural Control of the Circulation: Sex and Hypertension

描述(由申请人提供)：高血压患病率和发病机制的性别差异在人类和心血管疾病的动物模型中都有很好的记录。我们实验室的最新发现表明，向小鼠和大鼠体内注入低剂量的血管紧张素II或醛固酮会明显导致雄性比雌性更严重的高血压。此外，我们发现，卵巢摘除(OVX)取消了这些女性相关的降压作用，将雌激素或雌激素受体激动剂选择性地作用于雌激素受体a(Era)或雌激素受体b(Erb)进入大脑可以恢复对OVX女性的保护。集中注射雌激素可防止男性实验性高血压。在其他的初步研究中，我们发现，减少啮齿类动物大脑中的活性氧物种(ROS)或增加一氧化氮(NO)可以减轻由血管紧张素II或醛固酮全身治疗引起的高血压。目前的建议将通过解决以下问题来扩展这些独特的发现：1)雌激素在大脑中的哪个部位作用于其抗高血压保护？2)什么脑部雌激素受体亚型(S)对于这种抗高血压保护是必要的？3)[Ca~(2+)]i和改变ROS/NO平衡在雌激素保护作用的细胞调节中起什么作用？用来进行实验来回答这些问题的方法包括：对大鼠和小鼠血压和心率的慢性遥测测量，大鼠室旁核神经元的体外成像以确定雌激素对血管紧张素II和醛固酮诱导的血管紧张素II和醛固酮诱导的脑内细胞内[钙离子]i和[ROS]i的变化的影响(“标记的”)，假定的运动前交感神经元，药理学方法，用于选择性减弱大脑中雌激素受体亚型表达的小干扰RNA，以及通过基因操作选择性移除(敲除)ER1或ER2的小鼠。全面了解性别雌激素受体亚型和性激素在高血压发病机制中的作用的细胞和大脑机制，对于继续开发治疗心血管疾病的男性和女性至关重要。 公共卫生相关性：高血压是心脏病、中风、动脉粥样硬化、肾脏疾病和失明的主要危险因素。有大量证据表明，与男性相比，育龄女性对高血压有保护作用，新的证据表明，这种保护的部分原因是雌激素对中枢神经系统的作用，了解雌激素对大脑预防高血压的作用可能会导致预防和治疗这种疾病的新方法。

DESCRIPTION (provided by applicant): Sex differences in the prevalence and pathogenesis of hypertension are well documented in humans and in animal models of cardiovascular disease. Recent findings from our laboratory indicate that infusions of low doses of angiotensin II or of aldosterone into mice and rats produce markedly greater hypertension in males than in females. In addition, we find that ovariectomy (OVX) abolishes these female-related antihypertensive effects and that administration of estrogen or estrogen receptor agonists selective for estrogen receptor a (ERa) or for estrogen receptor b (ERb) into the brain restores protection in OVX females. Central administration of estrogen prevents experimentally-induced hypertension in males. In other preliminary studies we have found that either decreasing reactive oxygen species (ROS) or increasing nitric oxide (NO) in the brains of rodents attenuates hypertension induced by systemic treatment with angiotensin II or aldosterone. The present proposal will extend these unique findings by addressing the following questions: 1) Where does estrogen act in the brain to evoke its antihypertensive protection? 2) What brain estrogen receptor subtype(s) is/are necessary for this antihypertensive protection? and 3) What are the roles of [Ca2+]i and of altering the balance between ROS and NO in the cellular mediation of estrogen's protective effects? Methods to be used in conducting experiments to answer these questions include: chronic telemetric measurements of blood pressure and heart rate in rats and mice, in vitro imaging of rat paraventricular nucleus neurons to determine the effects of estrogen on angiotensin II- and aldosterone-induced changes in [Ca2+]i and [ROS]i in anatomically identified ("tagged"), putative premotor sympathetic neurons, pharmacological methods, small interference RNA to selectively attenuate expression of estrogen receptor subtypes in the brain, and genetically manipulated mice to selectively remove (knockout) ER1 or ER2. A full understanding of cellular and brain mechanisms underlying the effects of sex estrogen receptor subtypes, and sex steroids in the pathogenesis of hypertension is critical for the continued development of therapies to treat cardiovascular disease in both men and women. PUBLIC HEALTH RELEVANCE: Hypertension is a major risk factor for heart disease, stroke, atherosclerosis, renal disease and blindness. There is a substantial body of evidence indicating that females of child bearing age in comparison to males are protected against high blood pressure and new evidence indicates that part of this protection results from the action of estrogen on the central nervous system Understanding the role of estrogen on the brain to prevent high blood pressure is likely to lead to new methods for prevention and treatment of this disorder.