Mechanisms of Vascular Dysfunction with Advancing Reproductive Age

项目摘要/摘要 随着生育年龄的增加，卵巢功能的丧失和性激素的波动 会增加血管功能障碍的易感性。重要的是，内皮功能受损 在绝经前，特别是在围绝经期早期表现出来。然而， 内皮功能下降背后的机制尚不清楚。本R01的目的是为了 研究女性进展期内皮功能受损的主要机制 生殖年龄，特别是内皮素-1(ET-1)和雌二醇(E_2)之间的相互作用。这个 总的假设是ET-1的激活和ETB介导的扩张的丧失在 随着生育年龄的增加，血管内皮功能受损，而服用雌二醇组 在围绝经期会减弱这些反应。因此，该项目的第一个目标将测试 随着生育年龄的增加，假设ET-1导致内皮功能受损。第二 该项目的目的是验证ETB受体的改变有助于内皮受损的假设 随着生育年龄的增加而起作用。第三个目标将检验雌激素调节ET-1的假设 内皮功能的受体调控。我们将使用横截面设计来衡量宏观和微观 绝经前、围绝经期早期、围绝经期晚期和 绝经后妇女(根据生育年龄分类)在控制条件下并对 ETB受体和ETA受体被阻断。此外，我们还将进行静脉内皮细胞活检，以 检测内皮细胞内ET-1蛋白和ETB受体的表达。目标3将 通过使用受控的激素干预来更好地分离 雌激素对围绝经期早期和晚期妇女内皮功能和ET-1受体反应的影响。 这项对ET-1系统的全面评估将提供有关机制的新信息 导致女性血管功能障碍的因素，以及在特定时间内雌激素治疗对这些途径的影响 跨越更年期过渡的点。鉴于最近围绕荷尔蒙治疗的争议 女性，了解血管内皮细胞功能受损的机制 生育年龄对于确定合适的生育时间范围具有生理和临床上的重要性。 干预和优化激素治疗的益处。

PROJECT SUMMARY/ABSTRACT With advancing reproductive age, there is a loss of ovarian function and fluctuations in sex steroids that contribute to a greater susceptibility of vascular dysfunction. Importantly, impairments in endothelial function have been demonstrated before menopause, and specifically in the early peri-menopause transition. However, the mechanisms underlying this decline in endothelial function are not known. The purpose of this R01 is to examine key mechanisms contributing to impaired endothelial function in women advancing across reproductive ages, and in particular, the interactions between endothelin-1 (ET-1) and estradiol (E2). The overall hypothesis is that activation of ET-1 and a loss of ETB mediated dilation play a primary role in contributing to impaired endothelial function with advancing reproductive age, and that E2 administration during peri-menopause will attenuate these responses. Accordingly, the first aim of this project will test the hypothesis that ET-1 contributes to impaired endothelial function with advancing reproductive age. The second aim of this project will test the hypothesis that alterations in ETB receptors contribute to impaired endothelial function with advancing reproductive age. The third aim will test the hypothesis that E2 modulates ET-1 receptor control of endothelial function. We will use a cross-sectional design to measure macro- and micro- vascular endothelial-dependent dilation in premenopausal, early peri-menopausal, late peri-menopausal, and postmenopausal women (classified based on reproductive age) under control conditions and in response to ETB receptor and ETA receptor blockade. In addition, we will perform venous endothelial cell biopsies to assess intracellular ET-1 protein expression and ETB receptor expression in endothelial cells. Aim 3 will expand on these cross-sectional comparisons by using a controlled hormone intervention to better isolate the effects of E2 on endothelial function and ET-1 receptor responses in early and late peri-menopausal women. This comprehensive assessment of the ET-1 system will provide novel information on the mechanisms contributing to vascular dysfunction in women, and the impact of E2 therapy on these pathways at specific time points across the menopausal transition. Given the recent controversy surrounding hormone therapy in women, understanding the mechanisms contributing to impaired endothelial function with advancing reproductive age is of both physiological and clinical importance to identify an appropriate time frame for intervention and to optimize the benefits of hormone therapy.