Gonadotropins in a female model of age-induced hypertension

促性腺激素在女性老年高血压模型中的作用

• 批准号: 8104853
• 负责人: Kathryn L Sandberg
• 金额: $ 23.03万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8104853
• 关键词: Address; Adipose tissue; Adverse effects; Age; Aging; Animal Model; Attenuated; Automobile Driving; Awareness; Basic Science; Biological; Blood Pressure; Blood Vessels; Body Weight; Dahl Hypertensive Rats; Dependency; Disease; Drops; Estradiol; Experimental Models; Feedback; Female; Figs - dietary; Follicle Stimulating Hormone; Functional disorder; Gene Expression; Genes; Genomics; Gonadal Hormones; Gonadal structure; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Health; Hormones; Hypertension; Hypothalamic Hormones; Hypothalamic structure; Insulin; Kidney; Kidney Diseases; Lead; Life; Liver; Longevity; Luteinizing Hormone; Menopause; Modeling; Obesity; Ovarian; Ovarian Follicle; Ovarian hormone; Ovariectomy; Oxidative Stress; Pituitary Gland; Pituitary Hormones; Play; Postmenopause; Premenopause; Prevalence; Progesterone; Publishing; Rattus; Renal Tissue; Renin-Angiotensin System; Reporting; Research; Risk; Rodent Model; Role; Sex Chromosomes; Signal Transduction; Sodium-Restricted Diet; Surveys; Testing; Therapeutic; Tissues; Vascular Diseases; Vasoconstrictor Agents; Weight maintenance regimen; Woman; Women' s Health; age effect; aged; arm; blood pressure regulation; clinically significant; design; dosage; drug efficacy; experience; hormone deficiency; hormone regulation; hypothalamic pituitary ovarian axis; improved; insight; kidney vascular structure; male; men; neglect; normal aging; novel therapeutics; nutrition; prevent; response; salt sensitive; sex

DESCRIPTION (provided by applicant): This project addresses the PA-10-015 by proposing to investigate the role and mechanisms of follicle stimulating hormone (FSH) and leutinizing hormone (LH) in the age-induced increase in blood pressure (BP) and body weight (BW) observed in the female Dahl salt-sensitive (DS) rat. We have previously shown that ovariectomy accelerates the age-induced increase in BP and BW in this model and that 172-estradiol (E2) prevents these effects. Aging and ovariectomy, however, also result in a marked rise in FSH and LH. Though some studies implicate these pituitary hormones in BP regulation, their mechanisms of action are poorly understood. These proposed studies will provide key insight into this experimental model of female aging and postmenopausal hypertension. Aim 1 will determine if preventing the rise in FSH & LH that occurs as a result of ovarian hormone deficiency during normal aging from 4 months old (mo) to 12 mo in the female DS rat will attenuate the age-associated increase in BP, BW, insulin insensitivity, endothelial dysfunction, renal oxidative stress and activation of the vasoconstrictor arm of the renin angiotensin system (RAS) in vascular, renal and adipose tissues. We will also investigate the E2 and progesterone (P4) dependency of these pituitary hormone effects. Aim 2 will serve as the corollary to Aim 1 and will determine if increasing FSH & LH in young (3-4 mo) female DS rats will result in an increase in BP, BW, insulin insensitivity, endothelial dysfunction, renal oxidative stress and activation of the vasoconstrictor arm of the RAS in vascular, renal and adipose tissues. The clinical significance of this research is the insight it will provide into the mechanisms underlying the marked rise in the prevalence of hypertension in women as they age and after their transition into menopause. PUBLIC HEALTH RELEVANCE: This project is designed to make new discoveries into why age increases blood pressure and the prevalence of hypertension across the female lifespan. We will make these new discoveries by studying the role of the neglected gonadotropins in the age-induced increase in blood pressure that is observed in the Dahl salt-sensitive female rat maintained on a low sodium diet. Animal models of female aging are currently limited in number. Hopefully, furthering our understanding of this experimental model will lead to a greater use of this animal model in aging research on females. Furthermore, by investigating the gonadotropin hormone mechanisms responsible for the age-induced increase in blood pressure and hypertension, we may open the door to developing new therapeutic treatments for post-menopausal women and women with ovarian hormone deficiency - both of which experience marked changes in their gonadotropin profile from the ovarian hormone replete state.

描述（由申请人提供）：该项目针对 PA-10-015，提议研究促卵泡激素 (FSH) 和促黄体生成素 (LH) 在雌性 Dahl 盐敏感 (DS) 大鼠中观察到的年龄引起的血压 (BP) 和体重 (BW) 增加中的作用和机制。我们之前已经表明，在该模型中，卵巢切除术会加速年龄引起的血压和体重增加，而 172-雌二醇 (E2) 可以防止这些影响。然而，衰老和卵巢切除也会导致 FSH 和 LH 显着升高。尽管一些研究表明这些垂体激素与血压调节有关，但人们对它们的作用机制知之甚少。这些拟议的研究将为女性衰老和绝经后高血压的实验模型提供重要的见解。目标 1 将确定，在雌性 DS 大鼠中，在 4 个月至 12 个月的正常衰老过程中，预防由于卵巢激素缺乏而导致的 FSH 和 LH 升高是否会减轻与年龄相关的血压、体重、胰岛素不敏感、内皮功能障碍、肾脏氧化应激以及肾素血管紧张素系统 (RAS) 血管收缩臂的激活。 血管、肾和脂肪组织。我们还将研究这些垂体激素效应对 E2 和孕酮 (P4) 的依赖性。目标 2 将作为目标 1 的推论，并将确定年轻（3-4 个月）雌性 DS 大鼠中 FSH 和 LH 的增加是否会导致血压、体重、胰岛素不敏感、内皮功能障碍、肾脏氧化应激以及血管、肾脏和脂肪组织中 RAS 血管收缩臂的激活增加。这项研究的临床意义在于，它将深入了解女性随着年龄增长和进入更年期后高血压患病率显着上升的机制。 公共卫生相关性：该项目旨在对为什么年龄会增加血压以及女性一生中高血压的患病率做出新的发现。我们将通过研究被忽视的促性腺激素在年龄引起的血压升高中的作用来获得这些新发现，这种作用是在维持低钠饮食的达尔盐敏感雌性大鼠中观察到的。女性衰老的动物模型目前数量有限。希望进一步了解这个实验模型将导致这种动物模型在女性衰老研究中得到更多的应用。此外，通过研究导致年龄引起的血压和高血压升高的促性腺激素机制，我们可能为开发针对绝经后妇女和卵巢激素缺乏的妇女的新治疗方法打开了大门——这两种妇女的促性腺激素谱均与卵巢激素充足状态相比发生了显着变化。