Gonadotropins in a female model of age-induced hypertension

描述(由申请人提供)：本项目针对PA-10-015，建议研究卵泡刺激素(FSH)和促黄体生成素(LH)在观察到的雌性Dahl盐敏感(DS)大鼠年龄诱导的血压(BP)和体重(BW)增加中的作用和机制。我们以前已经证明，在这个模型中，卵巢切除加速了年龄引起的血压和体重的增加，而172-雌二醇(E2)可以阻止这些影响。然而，衰老和卵巢切除也会导致卵泡刺激素和促黄体生成素显著升高。尽管一些研究表明这些脑下垂体激素与血压调节有关，但它们的作用机制却知之甚少。这些拟议的研究将为这一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确定阻止雌性DS大鼠在4个月龄至12个月龄期间因卵巢激素缺乏而导致的FSH和LH值升高，是否能减轻血管、肾脏和脂肪组织中与年龄相关的BP、BW、胰岛素不敏感、内皮功能障碍、肾脏氧化应激和肾素血管紧张素系统(RAS)血管收缩臂的激活。我们还将研究E2和孕酮(P4)对这些脑下垂体激素影响的依赖性。目的2将作为目标1的推论，并将确定增加幼年(3-4个月)雌性DS大鼠的FSH和LH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的血管收缩臂的激活。这项研究的临床意义在于，它将为女性高血压患病率随着年龄增长和进入更年期后显着上升的机制提供洞察力。 公共卫生相关性：该项目旨在对为什么年龄会增加血压和高血压在女性寿命中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维持低钠饮食的Dahl盐敏感雌性大鼠的年龄诱导的血压升高中的作用来做出这些新的发现。目前，研究女性衰老的动物模型数量有限。希望我们对这一实验模型的进一步理解将导致更多地使用这一动物模型来研究女性的衰老。此外，通过研究导致年龄引起的血压升高和高血压的促性腺激素机制，我们可能会为绝经后妇女和卵巢激素缺乏的妇女开发新的治疗方法--这两者都经历了从卵巢激素充足状态到促性腺激素水平的显著变化。

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.