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）：该项目通过提议研究卵泡刺激激素（FSH）的作用和机制来解决PA-10-015，并在年龄诱导的血压升高（BP）和体重（BW）中观察到的女性DAHL盐盐敏感（DS ds）的升高（BP）和体重（BW）。我们先前已经表明，在该模型中，卵巢切除术加速了BP和BW的年龄诱导的增加，并且172-雌二醇（E2）阻止了这些影响。然而，衰老和卵巢切除术也导致FSH和LH显着增加。尽管一些研究暗示了这些垂体激素在BP调节中，但它们的作用机理知之甚少。这些提出的研究将为这种实验模型提供女性衰老和绝经后高血压的实验模型的重要见解。 AIM 1将确定是否防止雌性DS大鼠正常衰老的卵巢激素缺乏症在正常衰老中发生的FSH＆LH上升是否会减弱BP，BW，BW，胰岛素不敏感性，内皮功能障碍，肾脏氧化度和激活的繁殖量的增长，这会减轻与年龄相关的增长。血管，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。 AIM 2将作为AIM 1的推论，并确定年轻（3-4个MO）女性DS大鼠的FSH＆LH是否会导致BP，BW，胰岛素不敏感性，肾脏功能障碍，肾脏氧化应激，肾脏氧化应激和Ras在血管中肾脏，肾小管，肾小管组织中的血管加速臂的激活。这项研究的临床意义在于，它将对妇女年龄和过渡到更年期后高血压患病率显着上升的机制提供洞察力。 公共卫生相关性：该项目旨在使新发现使年龄增加血压和女性寿命中的高血压患病率。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做出这些新发现，这在低钠饮食中维持的DAHL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，进一步了解我们对这个实验模型的理解将导致对女性的衰老研究中的这种动物模型更多地使用。此外，通过调查负责年龄引起的血压和高血压升高的促性腺激素激素机制，我们可能为在绝经后妇女开发新的治疗方法和卵巢激素缺乏症的妇女开辟了大门 - 这两者都体验了其肿瘤状态型卵巢葡萄糖概况的变化。