Mechanisms of hypertension in women with polycystic ovary syndrome

摘要（家长补助金） 多囊卵巢综合征（PCOS）是最常见的生殖内分泌疾病，影响十分之一 育龄妇女。大约75%的PCOS女性有更严重的生殖和 代谢性PCOS表型，其以高雄激素血症的特征为主，包括胰岛素 胰岛素抵抗（IR）、代偿性高胰岛素血症、肥胖、皮下和内脏脂肪过多、血脂异常， 以及收缩压和舒张压升高和代谢综合征。在患有雄激素的肥胖女性中 过度（AE）-PCOS，外周血管交感神经活动增加。重要的是，游离血浆 睾酮水平是交感神经系统（SNS）介导的血压升高的预测因子， AE-PCOS女性患者的肾素血管紧张素系统（RAS）激活。通过这种应用，我们提出了新颖的 目的探讨雄激素对交感神经降压作用的影响机制 在AE-PCOS女性和我们的新型高雄激素血症雌性（HAF）大鼠模型中进行对照。 我们的总体假设是，AE-PCOS女性雄激素过多导致交感神经系统增强， 引起α-肾上腺素能血管收缩和肾交感神经系统激活， 增加血压。雄激素过量也会增加血管紧张素原的合成，反过来， 刺激RAS活性也增加血压。我们将在患有AE-PCOS的女性中测试这些假设 并在我们的HAF大鼠模型中以翻译的方式评估机制。目标1检验假设， 雄激素环境是与α-肾上腺素能血管收缩相关的交感神经激活的主要驱动力， AE-PCOS和HAF大鼠的压力反射敏感性和血压升高。目标2检验假设 这种雄激素驱动的交感神经激活增加了AE-PCOS和HAF大鼠的RAS活性和血压。一 这项提议最令人兴奋、最重要和最新颖的方面是令人信服的初步数据，这些数据表明， α1，β 1，2-肾上腺素受体阻滞剂和肾脏去神经支配可减弱血压升高， 与我们的数据一致，显示睾酮抑制可降低血压，并抑制RAS 和AE-PCOS妇女的SNSA。其重点是神经和肾脏控制机制的整合 AE-PCOS的血压，及其转化研究，伴随着分子研究， 该建议偏离了血压调节的标准研究。最重要的是，我们应该 证明雄激素，SNSA和RAS之间的关系，交感神经活动的调节可能是一个重要的因素。 有价值的治疗，以抑制AE-PCOS的根本原因。

ABSTRACT (Parent Grant) Polycystic ovary syndrome (PCOS) is the most common reproductive endocrinopathy, affecting 1 in 10 reproductive age women. Approximately 75% of women with PCOS have the more severe reproductive and metabolic PCOS phenotype, which is dominated by features of hyperandrogenism, which include insulin resistance (IR), compensatory hyperinsulinemia, obesity, subcutaneous and visceral adiposity, dyslipidemia, as well as increased systolic and diastolic blood pressure and metabolic syndrome. In obese women with androgen excess (AE)-PCOS, peripheral vascular sympathetic nerve activity is increased. Importantly, free plasma testosterone level is a predictor of sympathetic nervous system (SNS)-mediated increases in blood pressure and renin angiotensin system (RAS) activation in women with AE-PCOS. With this application we propose novel Aims to discover the mechanisms for the androgen effects on the sympathetic contribution to blood pressure control in women with AE-PCOS and in our novel hyperandrogenemic female (HAF) rat model. Our overall hypothesis is that androgen excess in women with AE-PCOS leads to increased sympathetic activation that causes α-adrenergic vasoconstriction and renal sympathetic nervous system activation to increase blood pressure. Androgen excess also increases angiotensinogen synthesis that would, in turn, stimulate RAS activity also increasing blood pressure. We will test these hypotheses in women with AE-PCOS and in a translational manner evaluate mechanisms in our HAF rat model. Aim 1 tests the hypothesis that the androgenic milieu is the primary driver for sympathetic activation associated with α-adrenergic vasoconstriction, baroreflex sensitivity and increased blood pressure in AE-PCOS and in the HAF rats. Aim 2 tests the hypothesis that this androgen-driven sympathetic activation increases RAS activity and BP in AE-PCOS and the HAF rat. A most exciting, significant and novel aspect of this proposal is the compelling preliminary data demonstrating that increases in blood pressure are attenuated by α1, β1,2-adrenoceptor blockade and by renal denervation, which is consistent with our data showing testosterone suppression decreases blood pressure, and suppresses the RAS and the SNSA in women with AE-PCOS. With its focus on the integration of neural and renal control mechanisms of blood pressure in AE-PCOS, and its translational studies, concomitant with molecular investigations, this proposal is a departure from standard investigations of blood pressure regulation. Most importantly, should we demonstrate a relationship between androgens, SNSA and RAS, modulation of sympathetic activity could be a valuable treatment to inhibit the underlying causes of AE-PCOS.