monal Mechanisms of Postmenopausal Hypertension

绝经后血压升高，但绝经后（PM）的机制 高血压未知。在上一个资助期间，我们描述了PM高血压模型的特征， 老年雌性自发性高血压大鼠（postmenopausal rat，PMR）。PMR停止发情周期 到12个月大时，血压和血浆睾酮水平升高，血浆睾酮水平降低， 雌二醇，肾血管阻力增加，GFR和肾血浆流量降低。虽然PMR 具有女性PM高血压的许多特征，介导血液中 PMR的压力仍不清楚。PMR中血压升高的一种机制是通过 血管活性花生四烯酸代谢物20-羟基二十碳四烯酸（20-HETE）的增加， 在肾脏中主要由细胞色素P450（CYP）4A ω-羟化酶产生。20-HETE导致肾脏 血管收缩，在初步研究中，CYP 4A ω-羟化酶的两种抑制剂降低了血液中的 PMR的压力高于年轻女性。虽然我们的数据表明，20-HETE介导高血压， PMR，负责增加20-HETE的机制尚不清楚。在上一个供资期间， 我们确定睾酮、血管紧张素II（Ang II）和内皮素有助于PMR中的高血压， 我们的初步研究表明，20-HETE可能通过睾酮、血管紧张素II和内皮素增加。在 PMR，血浆睾酮增加，雄激素受体拮抗剂降低血压，CYP 4A 2，主要 PMR中肾小球前血管系统中受睾酮控制的CYP 4A酶增加2倍。 PMR患者血浆肾素活性增加，阻断AT 1受体可降低血压 比年轻的女性。PMR时肾内内皮素增加，阻断内皮素ETA受体 降低PMR患者的血压，但对年轻女性无效。我们的初步数据表明，20-HETE有助于血管紧张素转换酶， II和内皮素介导的PMR高血压。最后，20-HETE的血管收缩作用是 假设涉及表皮生长因子受体（EGFR）的活化。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 雄激素受体的表达增加PMR的肾脏。这一建议的主要假设是 睾酮增加20-HETE，引起肾血管收缩，导致PMR高血压; 睾酮通过增加CYP 4A 2的表达直接增加20-HETE，和/或通过增加CYP 4A 2的表达间接增加20-HETE。 肾内血管紧张素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。 这些假设将在下面进行检验

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