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（由申请方提供）：本项目通过研究促卵泡激素（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诱导的血压（BP）和体重（BW）升高中的作用和机制来解决PA-10-015。我们以前已经表明，卵巢切除术加速了年龄引起的血压和体重增加，在这个模型中，172-雌二醇（E2）防止这些影响。然而，衰老和卵巢切除术也会导致FSH和LH显著升高。虽然一些研究暗示这些垂体激素参与血压调节，但对其作用机制知之甚少。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关键的见解。目的1将确定在雌性DS大鼠中，在从4个月大（mo）至12个月的正常衰老期间，预防由于卵巢激素缺乏而发生的FSH和LH的升高是否会减弱与年龄相关的BP、BW、胰岛素不敏感性、内皮功能障碍、肾氧化应激和血管中的肾素血管紧张素系统（RAS）的血管收缩臂的激活的增加，肾脏和脂肪组织。我们还将研究这些垂体激素效应的E2和孕酮（P4）依赖性。目标2将作为目标1的必然结果，并将确定增加年轻（3-4个月）雌性DS大鼠的FSH和LH是否会导致BP、BW、胰岛素不敏感性、内皮功能障碍、肾氧化应激和血管、肾和脂肪组织中RAS血管收缩臂的激活增加。这项研究的临床意义在于，它将提供对女性高血压患病率随年龄增长和进入更年期后显著上升的机制的深入了解。 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进行新的发现。我们将通过研究被忽视的促性腺激素在年龄诱导的血压升高中的作用来做出这些新的发现，该血压升高在维持低钠饮食的达尔盐敏感雌性大鼠中观察到。女性衰老的动物模型目前数量有限。希望我们对这种实验模型的进一步了解将导致这种动物模型在女性衰老研究中的更多应用。此外，通过研究促性腺激素激素机制，负责年龄引起的血压和高血压的增加，我们可能会打开大门，开发新的治疗绝经后妇女和卵巢激素缺乏症的妇女-这两个经验显着的变化，在他们的促性腺激素曲线从卵巢激素充满状态。