Neural Control of the Circulation: Sex and Hypertension

描述（由申请方提供）：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动物模型中得到了充分的证明。我们实验室最近的研究结果表明，向小鼠和大鼠输注低剂量的血管紧张素II或醛固酮，雄性动物的高血压明显高于雌性动物。此外，我们发现卵巢切除术（OVX）消除了这些女性相关的抗高血压作用，并且向脑内给予雌激素或选择性雌激素受体a（ER a）或雌激素受体B（ER B）的雌激素受体激动剂可恢复对OVX女性的保护作用。雌激素中枢给药可预防男性实验性高血压。在其他的初步研究中，我们发现，无论是减少活性氧（ROS）或增加一氧化氮（NO）在啮齿动物的大脑减弱血管紧张素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）雌激素在大脑中的何处起作用以引起其抗高血压保护作用？2)什么样的脑雌激素受体亚型是这种降压保护所必需的？[Ca~（2+）] i和改变ROS和NO之间的平衡在雌激素保护作用的细胞介导中的作用是什么？进行实验以回答这些问题的方法包括：长期遥测大鼠和小鼠的血压和心率，体外成像大鼠室旁核神经元，以确定雌激素对血管紧张素II和醛固酮诱导的[Ca2 +] i和[ROS] i变化的影响，（"标记"）、推定的运动前交感神经元、药理学方法、选择性减弱脑中雌激素受体亚型表达的小干扰RNA，以及选择性去除（敲除）ER 1或ER 2的遗传操作小鼠。充分了解性雌激素受体亚型和性类固醇在高血压发病机制中的作用的细胞和脑机制对于治疗男性和女性心血管疾病的治疗方法的持续发展至关重要。 公共卫生相关性：高血压是心脏病、中风、动脉粥样硬化、肾病和失明的主要危险因素。有大量的证据表明，女性的生育年龄相比，男性是保护免受高血压和新的证据表明，这种保护的一部分，从行动的雌激素对中枢神经系统的了解雌激素对大脑的作用，以防止高血压可能会导致新的方法，预防和治疗这种疾病。

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.