Estrogen receptor-α mediates estrogen protection from angiotensin II-induced hypertension in conscious female mice

It has been shown that the female sex hormones have a protective role in the development of angiotensin II (ANG II)-induced hypertension. The present study tested the hypotheses that 1) the estrogen receptor-α (ERα) is involved in the protective effects of estrogen against ANG II-induced hypertension and 2) central ERs are involved. Blood pressure (BP) was measured in female mice with the use of telemetry implants. ANG II (800 ng·kg ^-1·min^-1) was administered subcutaneously via an osmotic pump. Baseline BP in the intact, ovariectomized (OVX) wild-type (WT) and ERα knockout (ERαKO) mice was similar; however, the increase in BP induced by ANG II was greater in OVX WT (23.0 ± 1.0 mmHg) and ERαKO mice (23.8 ± 2.5 mmHg) than in intact WT mice (10.1 ± 4.5 mmHg). In OVX WT mice, central infusion of 17β-estradiol (E₂; 30 μg·kg^-1·day^-1) attenuated the pressor effect of ANG II (7.0 ± 0.4 mmHg), and this protective effect of E ₂ was prevented by coadministration of ICI-182,780 (ICI; 1.5 μg·kg^-1·day^-1, 18.8 ± 1.5 mmHg), a nonselective ER antagonist. Furthermore, central, but not peripheral, infusions of ICI augmented the pressor effects of ANG II in intact WT mice (17.8 ± 4.2 mmHg). In contrast, the pressor effect of ANG II was unchanged in either central E₂-treated OVX ERαKO mice (19.0 ± 1.1 mmHg) or central ICI-treated intact ERαKO mice (19.6 ± 1.6 mmHg). Lastly, ganglionic blockade on day 7 after ANG II infusions resulted in a greater reduction in BP in OVX WT, central ER antagonist-treated intact WT, central E₂ + ICI-treated OVX WT, ERαKO, and central E_2- or ICI-treated ERαKO mice compared with that in intact WT mice given just ANG II. Together, these data indicate that ERα, especially central expression of the ER, mediates the protective effects of estrogen against ANG II-induced hypertension.