G-protein coupled estrogen receptor 1 contributes to suppression of angiotensin II hypertension via modulation of AMPA GluA1 in the hypothalamic paraventricular nucleus in a mouse model of post-menopause

Menopausal hypertension is a leading contributor to adverse health outcomes in women. Although heightened sympathetic activation is implicated in menopausal hypertension, the hypothalamic mechanisms underlying increased blood pressure during ovarian senescence and how this compares to males are not well understood. In this study, treatment with 4-vinylcyclohexene diepoxide (VCD) was used to induce a form of accelerated ovarian failure that parallels the hormonal trajectory of post-menopause (post-AOF). In post-AOF mice, hypertension resulting from 14-day angiotensin II (AngII) infusion was associated with an increase in AMPA GluA1 receptor-mediated, but not NMDA receptor-mediated, currents in sympathoexcitatory neurons in the paraventricular hypothalamic nucleus (PVN). Heightened GluA1 currents in hypertensive post-AOF mice appeared to be mediated by an uncoventional AMPA receptor-AKAP150-associated G-protein coupled estrogen receptor 1 (GPER1) signaling pathway. In male mice, the heightening of GluA1 signaling following hypertension also was dependent on AKAP150, but via the classical protein kinase A signaling pathway. Increased AMPA currents and hypertension were not affected by estrogen receptor beta agonists in post-AOF mice. These results show that both post-AOF and male mice show similar hypertensive responses to slow-pressor AngII but differ in GluA1-GPER1-mediated signaling pathways in the PVN. Moreover, the results in post-AOF mice contrast with prior reports of hypertensive female mice at an early stage of AOF comparable to perimenopause, suggesting that hypertension at early and late ovarian failure are associated with distinct hypothalamic ionotropic glutamate receptor-mediated signaling pathways.