Estradiol deficiency aggravates AngII-induced vascular remodeling by failing to inhibit GRK2 through ERα-mediated autophagy

Hypertension acts as a critical cardiovascular risk factor that drives vascular remodeling, which manifests as vascular media thickening triggered by excessive proliferation and migration of vascular smooth muscle cells. Angiotensin II promotes vascular remodeling by upregulating G protein-coupled receptor kinase 2. Estradiol deficiency, particularly among postmenopausal individuals, increases susceptibility to hypertension by overactivating the renin-angiotensin system, while the precise mechanism remains unkown. Here we show that estradiol inhibits G protein-coupled receptor kinase 2 to ameliorate hypertensive vascular remodeling. Ovariectomy in spontaneously hypertensive rats exacerbate hypertension, while estradiol supplementation significantly reduced blood pressure and attenuated vascular remodeling. Mechanistically, Estradiol downregulated G protein-coupled receptor kinase 2 expression, leading to decreased β-arrestin2 recruitment and ERK signaling, thereby reducing vascular smooth muscle cell proliferation and migration. Additionally, Autophagy or estrogen receptor α blockade abolishes the effects of estradiol on G protein-coupled receptor kinase 2 degradation. This study provides a potential therapeutic strategy for hypertensive vascular remodeling. Ji and colleagues show that estradiol (E2) enhances autophagy and ERalpha-AMPK signaling in a mouse model of hypertension and vascular remodeling.