Mechanisms of hypertension in women with polycystic ovary syndrome

多囊卵巢综合征女性高血压发病机制

• 批准号: 10088719
• 负责人: Jane F Reckelhoff
• 金额: $ 1.3万
• 依托单位: JOHN B. PIERCE LABORATORY, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10088719
• 关键词: Adrenergic Agents; Adrenergic Receptor; Affect; Age; Androgens; Angiotensinogen; Animals; Attenuated; Baroreflex; Basic Science; Blood Pressure; Blood Vessels; Compensatory Hyperinsulinemia; Data; Denervation; Diastolic blood pressure; Disease; Dyslipidemias; Female; Gonadal Steroid Hormones; Human; Hyperandrogenism; Hypertension; Infertility; Insulin Resistance; Investigation; Kidney; Mediating; Metabolic; Metabolic syndrome; Modeling; Molecular; Nerve; Obesity; Peripheral; Phenotype; Physiology; Plasma; Polycystic Ovary Syndrome; Rattus; Renin-Angiotensin System; Sympathetic Nervous System; System; Testing; Testosterone; Visceral; Woman; androgenic; blood pressure regulation; cardiovascular disorder risk; experimental study; novel; parent grant; relating to nervous system; reproductive; subcutaneous; translational study; vasoconstriction

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.

摘要（家长资助） 多囊卵巢综合症 (PCOS) 是最常见的生殖内分泌疾病，影响十分之一的人 育龄妇女。大约 75% 患有 PCOS 的女性患有更严重的生殖和疾病 代谢性 PCOS 表型，以高雄激素血症的特征为主，其中包括胰岛素 抵抗力（IR）、代偿性高胰岛素血症、肥胖、皮下和内脏肥胖、血脂异常等 以及收缩压和舒张压升高以及代谢综合征。患有雄激素的肥胖女性 过量（AE）-PCOS，周围血管交感神经活动增加。重要的是，免费血浆 睾酮水平是交感神经系统 (SNS) 介导的血压升高和血压升高的预测因子 AE-PCOS 女性肾素血管紧张素系统 (RAS) 激活。通过这个应用程序，我们提出了新颖的 旨在发现雄激素影响交感神经血压的机制 AE-PCOS 女性和我们新型高雄激素血症雌性 (HAF) 大鼠模型中的控制。 我们的总体假设是，患有 AE-PCOS 的女性雄激素过多会导致交感神经增强 激活导致α-肾上腺素能血管收缩和肾交感神经系统激活 增加血压。雄激素过多也会增加血管紧张素原的合成，进而 刺激 RAS 活性也会导致血压升高。我们将在患有 AE-PCOS 的女性中测试这些假设 并以转化的方式评估我们的 HAF 大鼠模型中的机制。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。一个 该提案最令人兴奋、最重要和最新颖的方面是令人信服的初步数据表明： α1、β1,2-肾上腺素受体阻滞剂和肾去神经支配可以减弱血压的升高，这是 与我们的数据一致，显示睾酮抑制可降低血压并抑制 RAS 以及 AE-PCOS 女性的 SNSA。重点关注神经和肾脏控制机制的整合 AE-PCOS 中血压的影响及其转化研究，与分子研究相结合， 该提案背离了血压调节的标准研究。最重要的是，我们是否应该 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 抑制 AE-PCOS 根本原因的有价值的治疗方法。