T Cell-Mediated Regulation of Blood pressure In Postmenopausal Hypertension

心血管疾病是美国的主要死亡原因，高血压是其主要原因。 头号风险因素。在绝经后妇女中，雌激素的丢失 更年期极大地增加了这两种情况。虽然已知雌激素可以 是预防高血压和心血管疾病的主要保护因素 绝经前的雌性，它能够通过什么机制来发挥其 保护仍然不明确，并削弱了我们充分治疗或预防其 进展和严重程度。绝经后妇女对当前的抗生育药物反应不佳 高血压患者；%的女性在高血压时没有控制血压 更年期。我们最近证明，绝经前的女性受到保护 抗T细胞介导的高血压。我们现在证明，绝经后的女性 没有保护措施，T细胞介导的高血压在缺乏保护的情况下进展迅速 卵巢激素。确定雌激素通过哪些细胞机制 调节T细胞功能将发现一种新的重要的抗高血压药物 有助于开发新的治疗方法的途径 女性的心血管疾病。如下所述，有证据支持 认为这种保护是通过雌激素诱导的T调节信号来实现的 细胞，增加其抗炎和抗高血压基因的产生，以及 抑制反炎症型和高血压型T细胞功能 细胞。这项提案中概述的研究将调查性行为的中心假设 激素通过抑制T细胞减轻血管紧张素II的降压作用 渗透/激活，从而保护T细胞介导的高血压和肾脏 受伤。我们建议通过研究围绝经期到 绝经后，从高血压抵抗到高血压敏感，我们 可能会揭示导致绝经后的致病机制 高血压。我们将通过以下具体目标来检验这些假设1)确定 T细胞介导的高血压对雌激素受体的依赖性 绝经后的女性。我们将确定绝经后高血压和肾脏 损伤是通过T细胞上的ER受体而不是宿主肾脏介导的2)确定 T细胞亚群调节对绝经后高血压和肾脏的影响 受伤。雌激素可增加抗炎T细胞和抗炎作用 细胞因子的产生(IL-10)因此我们将使用更年期的VCD模型来确定 雌激素的丢失与促炎易感性的增加有关 细胞因子的产生与肾脏损伤。我们研究的翻译潜力很高：由 研究绝经后女性T细胞介导性高血压的发病情况 已发现的致病机制可能会导致新的治疗方法 绝经后女性的高血压相关并发症。

Cardiovascular disease is the leading cause of death in the U.S., and hypertension is its number one risk factor. In postmenopausal women, the loss of estrogen after menopause dramatically increases both of these conditions. While estrogen is known to be the major protective factor against hypertension and cardiovascular disease in premenopausal females, the mechanisms through which it is capable of exerting its protection remains ill-defined and impairs our ability to adequately treat or prevent its progression and severity. Postmenopausal women do not respond well to current anti- hypertensives; 64% of women do not have their blood pressure controlled when in menopause. We recently demonstrated that premenopausal females are protected against T cell mediated hypertension. We now show that postmenopausal females are not protected, and T cell mediated hypertension progresses rapidly in the absence of ovarian hormones. Determining the cellular mechanisms through which estrogen regulates T cell function would identify a novel and important anti-hypertensive pathway that would aid in the development of new therapeutic treatments for cardiovascular disease in women. As detailed below, there is evidence to support the notion that this protection is mediated through estrogen-induced signaling in T-regulatory cells, increasing their production of anti-inflammatory and anti-hypertensive genes, and repressing the function of opposing pro-inflammatory and pro-hypertensive types of T cells. The studies outlined in this proposal will investigate central hypothesis that sex hormones attenuate the hypertensive effects of angiotensin II by preventing T cell infiltration/activation, thus protecting against T cell mediated hypertension and renal injury. We propose that by studying the transition from perimenopause to postmenopause, so moving from hypertension resistance to hypertension sensitivity, we are likely to uncover the pathogenic mechanisms leading to postmenopausal hypertension. We will test these hypotheses via the following specific aims 1) Determine the estrogen receptor (ER) dependence of T cell mediated hypertension in postmenopausal females. We will determine if postmenopausal hypertension and renal injury are mediated via ER receptors on T cells versus the host kidney 2) Determine if modulation of T cell subtypes impacts postmenopausal hypertension and renal injury. Estrogen can increase anti-inflammatory T cells (Tregs) and anti-inflammatory cytokine production (IL-10) thus we will use the VCD model of menopause to determine loss of estrogen is associated with an increase in susceptibility to pro-inflammatory cytokine production and renal injury. Translational potential of our studies is high: by studying the onset of T cell-mediated hypertension in postmenopausal females, the pathogenic mechanisms uncovered may lead to novel treatments in decreasing hypertension-related complications in postmenopausal females.