Compromised microcirculation in women with Polycystic Ovary Syndrome

描述（由申请人提供）：多囊卵巢综合征（PCOS）是年轻女性中最常见的生殖内分泌疾病，影响6- 10%的育龄妇女。肥胖、胰岛素抵抗、高雄激素血症和高雌激素血症是PCOS的核心功能障碍，并使女性微血管功能障碍的风险增加。多囊卵巢综合征患者的内皮素-1（ET-1）循环浓度较高，ET-1是微循环（包括皮肤）中的一种有效血管收缩剂，可升高血压并导致内皮损伤。该建议的中心假设是睾酮对ET-1的影响介导了与PCOS相关的外周微血管功能障碍。将使用长时间皮肤加热模型来测试这一假设，以研究外周微血管反应性。局部皮肤加热已被广泛用于研究在许多生理条件下控制外周微循环的机制，包括肥胖、胰岛素抵抗和高血压。睾酮或ET-1对局部加热微血管反应性的影响尚未在患有或不患有PCOS的女性中进行研究。该提案旨在通过追求两个具体目标来提供这些缺失的信息。具体目标1将应用剂量-反应曲线来检查ET-1影响外周血管舒张的机制。具体目标2将确定睾酮影响PCOS患者和非PCOS患者外周微循环反应性的机制。这些研究将具有广泛的公共卫生意义，因为我们关于高雄激素血症对内皮功能的影响的研究结果可能提供适用于女性和男性心血管健康的见解。公共卫生相关性：患有多囊卵巢综合征（PCOS）的女性患心血管疾病的风险更大，特别是外周循环功能障碍，可导致高血压和葡萄糖代谢紊乱。这项研究将确定高雄激素血症在PCOS女性微血管反应性中的作用，以及睾酮可能影响内皮功能的机制。这些研究也具有广泛的公共卫生意义，因为我们关于高雄激素血症对内皮功能影响的研究结果可能提供可以改善所有肥胖女性和男性心血管健康的见解。

DESCRIPTION (provided by applicant): Polycystic ovary syndrome (PCOS) is the most common reproductive endocrinopathy in young women, affecting 6-10 % of women of reproductive age. Obesity, insulin resistance, hyperandrogenism and hyperestrogenism are core functional disorders of PCOS and place women at increased risk for microvascular dysfunction. Women with PCOS have greater circulating concentrations of endothelin-1 (ET-1), a potent vasoconstrictor in the microcirculation (including that of the skin), which can increase blood pressure and lead to endothelial damage. The central hypothesis of this proposal is that testosterone effects on ET-1 mediate the peripheral microvascular dysfunction associated with PCOS. This hypothesis will be tested using a prolonged skin heating model to study peripheral microvascular responsiveness. Local skin heating has been used extensively to study mechanisms controlling peripheral microcirculation under a number of physiological conditions, including obesity, insulin resistance and hypertension. The impact of testosterone or ET-1 on microvascular responsiveness to local heating has not been studied in women with or without PCOS. This proposal seeks to provide this missing information via pursuit of two Specific Aims. Specific Aim 1 will apply dose-response curves to examine the mechanism by which ET-1 influences peripheral vasodilation. Specific Aim 2 will determine the mechanism by which testosterone affects peripheral microcirculatory responsiveness in women with and without PCOS. These studies will have broad public health implications because our findings on the effect of hyperandrogenism on endothelial function may provide insights applicable to cardiovascular health in women and men. PUBLIC HEALTH RELEVANCE: Women with Polycystic Ovary Syndrome (PCOS) have greater risk for cardiovascular disease, in particular dysfunction of the peripheral circulation that can lead to hypertension and comprised glucose disposal. This research will determine the role of hyperandrogenism in microvascular responsiveness in women with PCOS, and the mechanisms by which testosterone may impact endothelial function. These studies also have broad public health implications because our findings on the effect of hyperandrogenism on endothelial function may provide insights that can improve cardiovascular health of all obese women and men.