0020 : Mechanisms of the protective effect of the estrogen receptor alpha in hypertension and aging

Background Cardiovascular diseases (CVD) incidence increases with aging and numerous risk factors like arterial hypertension. Estrogens reduce vascular damaging triggered by CVD like hypertension, mainly through estrogen receptor alpha (ERα). However, recent studies have shown that a fraction of ERα is located at the cell membrane where it initiates a Membrane Initiated Steroid Signaling (MISS). Both membrane and nuclear pathways of ERα seem to participate to the protective effect of estrogens but their respective role in hypertension is unknown. Objective This study aims to better understand the protective role of ERα in hypertension and its vascular consequences. Method Five groups of female mice were used in this study, each one lacking either estrogens (WT-OVX), ERα (ERα-KO), membrane-ERα (C451A-ERα) or ligand-dependent-transcriptional function of ERα (AF2°). Half of the mice received a chronic infusion of angiotensin II (0.5 mg/kg/d during 1 month) to induce moderate hypertension. Systolic blood pressure (SBP) and vascular structure were measured in KO mice and compared to wild-type mice (WT). Studies were performed in 5 months mice and 16 months mice in order to evaluate the impact of aging in the estrogens protection. Results SBP increased by 14 mmHg (ns) in WT mice. A similar increased was observed in C451A mice (20 mmHg, ns). By contrast, SBP increased significantly more in WT-OVX mice (31 mmHg, p=0,0007), ERα-KO (45 mmHg, p Conclusion Taken together, these data suggest that the protective effect of ERα against angiotensin II-induced hypertension depend on ERα gene transcription through AF2 and not membrane ERα signaling by contrast with most described vasculoprotective effects of estrogens. The author hereby declares no conflict of interest