Grace 

Perimenopause is a transition stage before menopause in which ovarian hormone production gradually declines. This period of a woman’s life has been associated with an increased risk of cardiovascular disease, including the development of hypertension. However, the neural mechanisms linking estrogen signaling to blood pressure regulation remain poorly understood. This study investigates the role of estrogen receptor beta (ERβ) signaling in the paraventricular nucleus (PVN) of the hypothalamus, a brain region involved in autonomic and cardiovascular regulation, in modulating neurogenic hypertension. To accurately recapitulate the gradual and irregular hormonal changes observed during perimenopause, female mice were treated with a drug that selectively depletes ovarian follicles over time, while age-matched males served as controls. Hypertension was induced via angiotensin II (AngII) infusion, a hormone known to raise blood pressure. Researchers then pharmacologically manipulated ERβ signaling within the PVN using both agonists (DPN, ERB-041, LQG) and antagonists (PHTPP). To understand the physiological and cellular effects of ERβ signaling, researchers measured systolic blood pressure, synaptic activity and oxidative stress. Electrophysiology was used to assess neuronal excitability, immunohistochemistry was used to identify relevant proteins and receptors within the PVN, and dihydroethidium (DHE) imaging was used to measure reactive oxygen species (ROS), a marker of oxidative stress. The results demonstrate that ERβ activation significantly attenuates AngII-induced increases in blood pressure in peri-AOF female mice, while producing minimal effects in males, indicating a clear sex-dependent hypertension protective mechanism. At the cellular level, ERβ activation reduced NMDA receptor-mediated excitatory currents in PVN neurons and suppressed reactive oxygen species (ROS) production, whereas ERβ inhibition produced the opposite effect, enhancing neuronal excitability and oxidative stress. These findings identify ERβ signaling in the PVN as a key regulator of synaptic excitability and oxidative stress in the control of neurogenic hypertension. The data supports a model in which ERβ activation exerts a sex-specific protective effect against AngII-induced hypertension during ovarian hormone decline. By simultaneously reducing NMDA receptor-mediated neuronal hyper excitability and limiting reaction oxygen species production, ERβ helps maintain autonomic balance within hypothalamic circuits that regulate cardiovascular function. These results highlight ERβ as a promising therapeutic target for mitigating hypertension risk during the perimenopausal transition.