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Estrogen receptor β contributes to both hypertension and hypothalamic plasticity in a mouse model of peri-menopause.

TitleEstrogen receptor β contributes to both hypertension and hypothalamic plasticity in a mouse model of peri-menopause.
Publication TypeJournal Article
Year of Publication2021
AuthorsMilner TA, Contoreggi NH, Yu F, Johnson MA, Wang G, Woods C, Mazid S, Van Kempen TA, Waters EM, McEwen BS, Korach KS, Glass MJ
JournalJ Neurosci
Date Published2021 May 03
ISSN1529-2401
Abstract

Hypertension susceptibility in women increases at the transition to menopause, termed perimenopause, a state characterized by erratic estrogen fluctuation and extended hormone cycles. Elucidating the role of estrogen signaling in the emergence of hypertension during perimenopause has been hindered by animal models that are confounded by abrupt estrogen cessation or effects of aging. In the present study, accelerated ovarian failure (AOF) in estrogen receptor beta (ERβ) reporter mice was induced by 4-vinylcyclohexene diepoxide (VCD) in young mice to model early-stage ovarian failure (peri-AOF) characteristic of peri-menopause. It was found that administering ERβ agonists suppressed elevated blood pressure in a model of neurogenic hypertension induced by angiotensin II (AngII) in peri-AOF, but not age-matched male mice. It was also found that ERβ agonist administration in peri-AOF females, but not males, suppressed the heightened NMDA receptor signaling and reactive oxygen production in ERβ neurons in the hypothalamic paraventricular nucleus (PVN), a critical neural regulator of blood pressure. It was further shown that deleting ERβ in the PVN of gonadally-intact females produced a phenotype marked by a sensitivity to AngII hypertension. These results suggest that ERβ signaling in the PVN plays an important role in blood pressure regulation in female mice and contributes to hypertension susceptibility in females at an early stage of ovarian failure comparable to human perimenopause.SIGNIFICANCE STATEMENTIn women, altered gonadal hormone signaling is implicated in the increased hypertension incidence associated with perimenopause. However, the role of estrogen signaling in perimenopausal hypertension is not well understood. We demonstrate that cyclic estrogen receptor beta (ERβ) agonist administration reverses hypertension susceptibility in a chemical model of perimenopause. We also show that the reduced hypertension in this model is associated with a suppression of NMDA receptor signaling in ERβ-expressing hypothalamic paraventricular nucleus (PVN) neurons in AngII treated-mice. Finally, deleting PVN ERβ in intact female mice produced a phenotype characterized by sensitivity to AngII hypertension. These results provide preclinical evidence supporting a therapeutic window of opportunity for management of hypertension by ERβ agonists as women transition through menopause.

DOI10.1523/JNEUROSCI.0164-21.2021
Alternate JournalJ Neurosci
PubMed ID33941651