Origins of sex differences in the mechanisms of obesity-associated hypertension

肥胖相关高血压机制中性别差异的起源

• 批准号: 10678441
• 负责人: Candee Barris
• 金额: $ 4.12万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678441
• 关键词: Adrenal Glands; Adult; Affect; Aldosterone; Anabolism; Atropine; Biology; Blood Pressure; Blood Vessels; CYP11B2 gene; Cardiovascular Diseases; Cardiovascular system; Cells; Clinical Data; Data; Dissociation; Endothelial Cells; Female; Four Core Genotypes; Funding; Gonadal Steroid Hormones; Health; Heart Rate; Human; Hypertension; In Vitro; Knowledge; Laboratories; Leptin; Measures; Mediating; Menopause; Mentorship; Mineralocorticoid Receptor; Modeling; Molecular; Mus; Myography; Obese Mice; Obesity; Outcome; Ovariectomy; Ovary; Phenotype; Physiology; Play; Ploidies; Premenopause; Production; Propranolol; Receptor Inhibition; Receptor Signaling; Recording of previous events; Reporting; Research; Risk Factors; Role; Sampling; Sex Chromosomes; Sex Differences; Signal Pathway; Signal Transduction; Source; Specificity; Testing; Therapeutic; Training; Universities; Vascular Diseases; Woman; adipokines; blood pressure control; blood pressure regulation; cardiovascular disorder risk; experimental study; female sex hormone; human female; hypertensive; improved; leptin receptor; male; mouse model; novel; obesity development; post-doctoral training; pre-doctoral; protective effect; response; sex; stem; steroidogenic acute regulatory protein; therapeutically effective

PROJECT SUMMARY Obesity, which affects more than 42% of adults in the US, is the leading risk factor for hypertension. While premenopausal women are commonly viewed as protected from hypertension and cardiovascular disease, compelling evidence establishes that obesity abrogates the protective effects of female sex and predisposes women to vascular dysfunction and hypertension. Obesity-associated hypertension (OAH) involves the adipokine leptin in both males and females but through sex-specific mechanisms. We have shown that leptin elevates sympathetic activity in males whereas it stimulates aldosterone production and leads to the activation of the mineralocorticoid receptor (MR) signaling in endothelial cells in obese female mice. Clinical data indicate that obese women have disproportionately high aldosterone levels and are more responsive to MR blockers. However, a critical gap in knowledge is the source of these sex differences. Preliminary studies revealed that the absence of female sex hormone production with gonadectomy (GDX) had no additional effect on obese female mice. This novel data suggest that OAH remains leptin-dependent and aldosterone-mediated in the absence of female sex hormones and that female sex steroids play a limited role in the control of the development of OAH. Based on these findings, the central hypothesis of this proposal is that female sex chromosomes potentiate the adrenal leptin-CYP11B2-aldosterone axis in obesity. This hypothesis will be tested in 2 aims. Aim 1 will test the hypothesis that female sex chromosomes predispose to leptin-mediated aldosterone production and hypertension. We will investigate the mechanisms controlling leptin and aldosterone production, as well as BP regulation and vascular function, in leptin-infused GDX four-core genotype mice, a model dissociating gonadal phenotype from sex chromosomes. Aim 2, will test the hypothesis that human female adrenals are predisposed to exacerbated aldosterone production in response to leptin and obesity. We will take advantage of our access to freshly obtained human adrenals and human adrenocortical cells to determine whether female sex and obesity predispose adrenals to leptin-mediated aldosterone production and investigate the effects of obesity, sex and menopause on the signaling pathways regulating aldosterone production. From these studies, we expect to identify a role for sex chromosome complement in the sex specificity of the mechanisms of OAH as well as demonstrate that human female adrenals are more sensitive to leptin-mediated aldosterone production than that of males. The project will be conducted under the co-mentorship of Dr. Eric Belin de Chantemèle and Dr. Jennifer Sullivan, Vascular Biology Center and Department of Physiology at Augusta University, which has a rich history of successful pre- and post-doctoral training. The proposed project is for 3 years of funding with the proposed aims divided amongst the 3 years of funding, culminating with a dissertation defense at the end of the third year. We anticipate that findings from this novel proposal will unmask the origin and provide new information about the mechanism for sex differences in hypertension in obese women and lead to improved therapies.

项目概要 肥胖影响着超过 42% 的美国成年人，是高血压的主要危险因素。尽管 绝经前妇女通常被认为可以预防高血压和心血管疾病， 令人信服的证据表明，肥胖会消除女性的保护作用，并导致 女性容易出现血管功能障碍和高血压。肥胖相关性高血压（OAH）涉及 脂肪因子瘦素在男性和女性中均存在，但通过性别特异性机制。我们已经证明瘦素 提高男性的交感神经活性，同时刺激醛固酮的产生并导致激活 肥胖雌性小鼠内皮细胞中盐皮质激素受体（MR）信号传导的研究。临床数据表明 肥胖女性的醛固酮水平异常高，并且对 MR 阻滞剂更敏感。 然而，知识上的重大差距是这些性别差异的根源。初步研究表明 性腺切除术（GDX）缺乏女性性激素的产生对肥胖没有额外的影响 雌性小鼠。这一新数据表明 OAH 在 缺乏女性性激素，女性性类固醇在控制发育方面的作用有限 OAH。基于这些发现，该提案的中心假设是女性性染色体 增强肥胖症中的肾上腺瘦素-CYP11B2-醛固酮轴。该假设将在两个目标中进行检验。目的 1 将检验女性性染色体易产生瘦素介导的醛固酮生成的假设 和高血压。我们将研究控制瘦素和醛固酮产生的机制，以及 瘦素输注的 GDX 四核基因型小鼠的血压调节和血管功能，一种解离模型 来自性染色体的性腺表型。目标 2，将检验人类女性肾上腺的假设 因瘦素和肥胖而容易加剧醛固酮的产生。我们将利用 我们使用新鲜获得的人类肾上腺和人类肾上腺皮质细胞来确定女性性别是否 肥胖使肾上腺容易产生瘦素介导的醛固酮，并研究肥胖的影响， 性和更年期对调节醛固酮产生的信号通路的影响。从这些研究中，我们期望 确定性染色体补体在 OAH 机制的性别特异性中的作用以及 证明人类女性肾上腺对瘦素介导的醛固酮产生比 男性。该项目将在 Eric Belin de Chantemèle 博士和 Jennifer 博士的共同指导下进行 Sullivan，奥古斯塔大学血管生物学中心和生理学系，历史悠久 成功的博士前和博士后培训。拟议项目的资助期限为 3 年 资助的目标分为三年，最终在第三年年底进行论文答辩。 我们预计这项新颖提案的发现将揭示其起源并提供有关的新信息 肥胖女性高血压性别差异的机制并导致治疗方法的改进。