monal Mechanisms of Postmenopausal Hypertension

绝经后血压升高，但绝经后(PM)的机制 高血压是未知的。在之前的资助期间，我们描述了PM高血压的模型， 老年雌性自发性高血压大鼠(绝经后大鼠，PMR)。PMR停止发情周期 到12个月龄时，表现出血压和血浆睾酮的升高，而血浆的下降 雌二醇，增加肾血管阻力，减少肾小球滤过率和肾血浆流量。而PMR 具有女性PM高血压的许多特征，调节血液增加的机制 PMR的压力仍不明朗。PMR中血压升高的一个机制是通过 血管活性花生四烯酸代谢产物20-羟基二十碳四烯酸(20-HETE)增加， 在肾脏中主要由细胞色素P450(CYP)4A辅羟基酶产生。20-HETE导致肾脏 血管收缩，在初步研究中，两种CYP4A辅羟基酶抑制剂降低血液 PMR的压力比年轻女性更大。尽管我们的数据表明20-HETE在高血压中起调节作用 PMR、20-HETE升高的机制尚不清楚。在上一次筹资期间， 我们确定睾酮、血管紧张素II(Ang II)和内皮素与PMR的高血压有关，并且 我们的初步研究表明，20-HETE可能通过睾酮、Ang II和内皮素增加。在……里面 PMR，血浆睾酮升高，雄激素受体拮抗剂降低血压，而主要的 在PMR中，肾小球前血管中受睾酮控制的CYP4A酶增加了2倍。 PMR患者血浆肾素活性增加，AT1受体阻断更能降低血压 而不是年轻的雌性。PMR时肾内内皮素升高，并阻断内皮素ETA受体 降低PMR中的血压，但不会降低年轻女性的血压。我们的初步数据显示，20-HETE对Ang和Ang PMR中II-和内皮素介导的高血压。最后，20-HETE的血管收缩作用是 推测与表皮生长因子受体(EGFR)的激活有关。雄激素受体可能 增强EGFR的磷酸化和活化，以响应20-HETE。在初步研究中，EGFR和 PMR患者肾脏雄激素受体表达增加。这项提议的核心假设是 睾酮增加20-HETE，导致肾血管收缩，导致PMR高血压； 睾酮通过增加CYP4A2的表达直接增加20-HETE和/或间接通过增加 肾内Ang II和内皮素；最后，睾酮增强20-HETE介导的肾血管收缩 通过增加EGFR的激活。 这些假设将在以下方面得到验证

Blood pressure increases following menopause, but the mechanisms responsible for postmenopausal (PM) hypertension are unknown. During the previous funding period, we characterized a model of PM hypertension, the aging female spontaneously hypertensive rat (postmenopausal rat, PMR). The PMR stop estrous cycling by 12 months of age, and exhibit increases in blood pressure and plasma testosterone, decreased plasma estradiol, increased renal vascular resistance with decreases in GFR and renal plasma flow. While the PMR has many of the characteristics of PM hypertension in women, the mechanisms mediating increases in blood pressure in the PMR remains unclear. One mechanism by which blood pressure could increase in PMR is via an increase in the vasoactive arachidonic acid metabolite, 20-hydroxyeicosatetraenoic acid (20-HETE), produced in the kidney mainly by cytochrome P450 (CYP)4A co-hydroxylases. 20-HETE causes renal vasoconstriction, and in preliminary studies, two inhibitors of the CYP4A co-hydroxylases decrease blood pressure more in PMR than young females. Although our data suggest that 20-HETE mediates hypertension in PMR, the mechanisms responsible for increased 20-HETE are not clear. During the previous funding period, we determined that testosterone, angiotensin II (Ang II) and endothelin contribute to hypertension in PMR, and our preliminary studies suggest that 20-HETE may be increased via testosterone, Ang II and endothelin. In PMR, plasma testosterone increases, an androgen receptor antagonist reduces BP, and CYP4A2, the major CYP4A enzyme in preglomerular vasculature that is controlled by testosterone, is increased 2 fold in PMR. Plasma renin activity is increased, and blockade of the AT1 receptor reduces blood pressure more in PMR than young females. Intrarenal endothelin is increased in PMR, and blockade of the endothelin ETA receptor reduces BP in PMR, but not young females. Our preliminary data show that 20-HETE contributes to both Ang II- and endothelin-mediated hypertension in PMR. Finally, the vasoconstrictor action of 20-HETE is hypothesized to involve activation of epidermal growth factor receptor (EGFR). Androgen receptor may enhance EGFR phosphorylation and activation in response to 20-HETE. In preliminary studies, EGFR and androgen receptor expression are increased in kidneys of PMR. The central hypotheses of this proposal are that testosterone increases 20-HETE causing renal vasoconstriction that leads to hypertension in PMR; testosterone directly increases 20-HETE by increasing expression of CYP4A2 and/or indirectly by increasing intrarenal Ang II and endothelin; and finally, testosterone enhances 20-HETE-mediated renal vasoconstriction by increasing EGFR activation. These hypotheses will be tested in the following