Contribution of G protein coupled estrogen receptor to changes in hypothalamic plasticity and hypertension susceptibility in mice with accelerated ovarian failure

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Although the increase in hypertension and cardiovascular disease-risk at menopause is well-recognized, the mechanisms of menopausal hypertension are still inadequately understood. Irregular cycles and declining levels of estrogen have been suspected to play a critical role in the emergence of hypertension at the onset of menopause. However, a clear understanding of estrogen’s role in menopausal hypertension has been limited by the confounding effects of variables such as aging in the human literature and the use of models primarily reliant on the use of ovariectomized animals that do not replicate natural menopause in the preclinical literature. Significantly, a mouse model of accelerated ovarian failure (AOF) induced by 4-vinylcyclohexene diepoxide (VCD) can recapitulate early (i.e., peri-AOF) and late (i.e., post-AOF) stages of human peri- and postmenopause, respectively. The AOF model has proven effective in isolating the role of sex hormones in blood pressure, particularly with respect to models of neurogenic hypertension involving the hypothalamic paraventricular nucleus (PVN), a brain area critical for coordinating sympathetic and neurohumoral processes important for the regulation of blood pressure. In the last grant award, we found that peri-AOF hypertension induced by slow- pressor angiotensin II (AngII) was associated with a signaling pathway involving estrogen receptor beta (ERb) and the NMDA-type glutamate receptor in PVN neurons. It is important to recognize that after perimenopause women transition to postmenopause, however, it is unclear if the mechanisms of hypertension during postmenopause are mediated by similar mechanisms. In pilot data, we show that hypertension at post-AOF is associated with altered signaling involving GluA1-expressing AMPA, but not NMDA receptors. We further show that administration of an agonist of the G-protein coupled estrogen receptor 1 (GPER), but not ERb, inhibits AngII hypertension in post-AOF mice. In this proposal, we will test the central hypothesis that post-AOF mice are predisposed to hypertension that is dependent on GluA1 plasticity in the PVN and alleviated by GPER signaling. Two aims will test this hypothesis. Aim 1 tests the sub-hypothesis that alterations in PVN GluA1 signaling contribute to hypertension in post-AOF mice. Aim 2 tests the sub-hypothesis that post-AOF hypertension is associated with GPER signaling in the PVN. These studies will be performed using a combination of approaches including high-resolution anatomical, neurophysiological, in vivo gene targeting, and single-cell RNA sequencing approaches.