Mechanisms of T cell-mediated hypertension in females and males

 描述(申请人提供)：高血压影响约33%的美国成年人，是心血管疾病的危险因素。只有不到40%的高血压患者用目前的药物控制他们的血压，60%的患者面临心血管疾病发病率和死亡率的高风险。尽管男女都会患上高血压，但年轻女性比年龄匹配的男性更容易患上高血压。确定女性延缓血压升高的机制是一种未得到充分利用的方法，可以用来为两性开发更好的治疗方案。提高血压控制率的一个关键障碍是缺乏关于推动两性血压升高的分子机制的知识。我们的目标是通过促进我们对T细胞在男性和女性血压控制中的作用的理解来解决这些差距。越来越多的人支持效应T细胞在雄性动物模型高血压中的因果作用。然而，我们报道了雌性自发性高血压大鼠(SHR)比雄性自发性高血压大鼠(SHR)拥有更多的调节性T细胞(Treg)。Treg限制了男性的血压升高，我们的初步数据显示，Treg的扩张降低了女性SHR的血压。我们的中心假设是，尽管效应性T细胞在两性中都会引起高血压，但女性体内更大的Treg通过增加白细胞介素10(IL-10)诱导的一氧化氮(NO)的产生来缓解T细胞介导的高血压。雄性动物的Treg介导的衰减性高血压与NO依赖的血管扩张增加有关，初步数据表明，只有雌性SHR的NOS活性增加伴随Tregs的增加。两个具体目标将检验我们的假设。目标1将检验这样一种假设，即女性的大三叉神经节限制了相对于男性的血压增加。我们将确定性别对肾脏和血管T细胞激活和功能的影响，并测量T细胞全耗尽和Treg耗尽/扩增后的血压反应、蛋白尿和血管功能。过继转移研究将确定来自男性和女性的T细胞是否存在影响分化的先天差异，或者当地环境在定义免疫特征方面是否更关键。肾移植研究将确定肾脏与决定T细胞类型的循环因素之间的作用。目的2将验证这一假设，即女性有更大的Treg介导的NO生物利用度通过IL-10增加，从而改善血管内皮细胞和肾功能。我们将在缺乏和存在IL-10阻滞剂的情况下，测量Treg耗尽/扩张后的生物利用度。我们将测量Treg和IL-10介导的NO释放对压力钠尿曲线和血管功能的贡献。我们将评估慢性一氧化氮合酶抑制期间Treg介导的NO产生对血压控制的贡献。结果将提供必要的临床前基础，以支持开发新的、更精细的方法，以性别特定的方式针对特定的免疫成分，以提高BP控制率。针对高血压的病理生理原因的治疗无疑将提高血压控制率，防止心血管疾病导致的过早死亡。

 DESCRIPTION (provided by applicant): Hypertension affects ~33% of adults in the U.S. and is a risk factor for cardiovascular disease. Fewer than 40% of hypertensive patients control their blood pressure (BP) with current medication, leaving 60% at heightened risk for cardiovascular morbidity and mortality. Although both sexes develop hypertension, young women are protected from hypertension relative to age-matched men. The identification of mechanisms by which females delay increases in BP is an underutilized approach that can be exploited to develop improved treatment options for both sexes. A critical barrier to improving BP control rates is the lack of knowledge regarding the molecular mechanisms driving elevated BP in either sex. Our goal is to address these gaps by advancing our understanding of the role of T cells in BP control in males and females. There is growing support for a causal role for effector T cells in hypertension in male animal models. Data in females are largely lacking, however, we reported that female spontaneously hypertensive rats (SHR) have more regulatory T cells (Tregs) than males. Tregs limit increases in BP in males and our preliminary data shows that Treg expansion decreases BP in female SHR. Our central hypothesis is that although effector T cells cause hypertension in both sexes, greater Tregs in females mitigate T cell-mediated hypertension via increased interleukin (IL)-10 induced nitric oxide (NO) production. Treg-mediated attenuation hypertension in male animals is associated with increased NO-dependent vasodilation, and preliminary data indicates NOS activity increases concomitant with increases in Tregs only in female SHR. Two Specific Aims will test our hypothesis. Aim 1 will test the hypothesis that greater Tregs in females limit increases in BP relative to males. We will determine the impact of sex on renal and vascular T cell activation and function and measure BP responses, proteinuria, and vascular function following total T cell depletion and Treg depletion/expansion. Adoptive transfer studies will determine if T cells from males vs. females have innate differences impacting differentiation, or if the local environment is more critical in defining the immune profile. Renal transplant studies will determine of the role of the kidney vs. circulating factors n defining T cell profiles. Aim 2 will test the hypothesis that females have greater Treg-mediated increase in NO bioavailability via IL-10 resulting in improved vascular endothelial and renal function. We will measure NO bioavailability following Treg depletion/expansion in the absence and presence of IL-10 blockers. We will measure the contribution of Treg and IL-10-mediated NO release on the pressure natriuresis curve and vascular function. We will assess the contribution of Treg-mediated NO production on BP control during chronic NOS inhibition. Results will provide necessary pre-clinical foundation to support the development of novel, more refined approaches to target specific immune components in a sex- specific manner to improve BP control rates. Therapies targeting the pathophysiological cause of hypertension will undoubtedly improve BP control rates and prevent premature death from cardiovascular disease.