Estradiol via GPER Maintains Protection Against Arterial Stiffening During Midlife Hypertension in a Mouse Model of Menopause

Endogenous estradiol is associated with cardiovascular protection, but whether menopausal hormone therapy provides protection in aging women with underlying cardiometabolic disease is still not known. Our previous work has shown that the membrane-bound G protein-coupled estrogen receptor (GPER) plays a crucial role in estradiol's protective vascular effects by promoting vasodilation, attenuating oxidative stress, and reducing arterial stiffness. In the current study, we designed a midlife mouse model of menopause with induced hypertension to more closely mimic the conditions of postmenopausal women in randomized clinical trials. We hypothesized that estradiol's vascular protection would be reduced in the presence of cardiovascular disease, especially when the disease was established before menopause, and that vascular GPER plays a role in the response. Middle-aged female C57Bl/6J mice, wildtype and global GPER knockout mice, and smooth muscle-specific GPER knockout mice were ovariectomized at 46 weeks of age and infused with Ang II to induce hypertension in combination with either estradiol or vehicle treatment. Estradiol did not significantly impact blood pressure but reduced arterial stiffness independent of the timing of hypertension. Either global or smooth muscle cell GPER deletion abrogated estradiol's protection from arterial stiffening. These studies are important for determining whether cardiovascular status should be a factor when considering menopausal hormone therapy and underscores GPER as an important mediator of estradiol's protective vascular effects, particularly with regards to arterial stiffness.