Presently, there is limited information on the effects of estrogen on the development and progression of hypertension. The increased incidence of hypertension in women after age 50 suggests that endocrine changes associated with a decline in ovarian function play a role in the pathogenesis and clinical manifestations of hypertension. These issues have not been adequately addressed, and it is not clear whether estrogen is protective in regard to hypertension. Unquestionably, more than one system plays a role in the pathogenesis of hypertension. However, there are major derangements in the angiotensin system (RAS). We demonstrated in a model of postmenopausal chronic hormone replacement that estrogen (E2) both reduced the pressor response to angiotensin II (Ang II) and increased the magnitude of the vasodepressor actions of Ang-(1-7). Further, estrogen reduced angiotensin converting enzyme (ACE) mRNA in lung, kidney, and aorta, in conjunction with a decrease in ACE activity in tissues and serum, and in association with a reduction in circulating levels of Ang II and increased levels of Ang-(1-7). These findings provide the first evidence demonstrating that estrogen may be protective against hypertension by shifting the vasoconstrictor-vasodilator balance of the RAS. Our hypothesis is that estrogen contributes to the regulation of arterial pressure augmenting the local regional vasodilator contributions of Ang-(1-7) and diminishing the vasoconstrictor actions of Ang II. A critical component of this effect of estrogen may arise through its down-regulation of angiotensin converting enzyme. We will determine the mechanism for these effects of estrogen by: 1) testing whether estrogen augments regional vasodilatory vascular reactivity to Ang-(1-7); (2) determining whether estrogen increases the affinity and number of the novel non-AT1/non-AT2 angiotensin receptor; 3) determining whether estrogen alters local angiotensin metabolism; and 4) testing whether estrogen reduces ACE mRNA through the classical estrogen-receptor, ERalpha, or the novel estrogen receptor, ERbeta. These novel studies will enhance our understanding of the role estrogen plays in promoting the paracrine production and participation of Ang-(1-7) in the regulation of regional vascular resistance, and may provide a new rationale for the use of estrogen to prevent and treat cardiovascular disease in postmenopausal women.