monal Mechanisms of Postmenopausal Hypertension

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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