Estrogen Receptor β Contributes to Both Hypertension and Hypothalamic Plasticity in a Mouse Model of Peri-Menopause

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 b (ERb) reporter mice was induced by 4-vinylcyclohexene diepoxide in young mice to model early-stage ovarian failure (peri-AOF) characteristic of peri-menopause. It was found that administering ERb agonists suppressed elevated blood pressure in a model of neurogenic hypertension induced by angiotensin II (AngII) in peri-AOF, but not in age-matched male mice. It was also found that ERb agonist administration in peri-AOF females, but not males, suppressed the heightened NMDAR signaling and reactive oxygen production in ERb neurons in the hypothalamic paraventricular nucleus (PVN), a critical neural regulator of blood pressure. It was further shown that deleting ERb in the PVN of gonadally intact females produced a phenotype marked by a sensitivity to AngII hypertension. These results suggest that ERb 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.

Unraveling the role of Epac1‐SOCS3 signaling in the development of neonatal‐CRD‐induced visceral hypersensitivity in rats

“…However, albeit female animals could serve to mimic the female predominance of IBS in clinical scenario, the interference from estrogen and progesterone disturbances may affect the pain perception and underlying pain circuitry during the estrus cycle. Moreover, the circulating sex steroids may differentially modulate the estrogen receptor in the PVN, thus participating in the functional regulation and structural modification of PVN 39,40 . Accordingly, we only recruited male rats for experimentation.…”

“…Moreover, the circulating sex steroids may differentially modulate the estrogen receptor in the PVN, thus participating in the functional regulation and structural modification of PVN. 39 , 40 Accordingly, we only recruited male rats for experimentation. The male rats were housed in environment of a standard 12/12‐h light–dark cycle (lights on at 07:00 a.m.), controlled temperature (22°C), and humidity (50%).…”

Hypertension in Women

“…Estrogen receptors (ERα and ER β ) are found in all of the aforementioned brain centers involved in the central control of cardiovascular system (56,57) and according to the number of studies, their activation consequently leads to the sympathoinhibition.…”

“…The activation of ER β receptors in the PVN leads to decline in production of reactive oxygen species and activates the neural nitric oxide synthetase, promoting the production of nitric oxide (48,56). Exciting results from the recent study (57) reveal that the administration of ER β receptor agonist in the PVN of perimenopausal female mice prevents the increase in blood pressure in the angiotensin II-induced neurogenic hypertension. The importance of ER β receptor signaling in the modulation of central autonomic control is further confirmed by the findings that demonstrate that estradiol inhibits pressor effects originating from RVLM via activation of ER β /PI3K/Akt signaling pathway (60).…”

Obesity and Body Mass Components Influence Exercise Tolerance and the Course of Hypertension in Perimenopausal Women

“…During this period, female body prepares for menopause from fertile life. [ 5 ]. Multiple mechanisms activate the renin–angiotensin–aldosterone system (RAAS) in obesity, including compression of the kidneys and increased sympathetic nervous system (SNS) activation [ 6 ].…”