CO-46: Protective role of the estrogen receptor alpha during hypertension

Background Estrogens have protective effects in the cardiovascular system, as evidenced by the decreased incidence of cardiovascular diseases (CVD) in premenopausal compared with postmenopausal women. Estrogens reduce vascular damaging triggered by CVD like hypertension, through their nuclear receptors, mainly 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. This study aims to better understand the protective role of ERα in hypertension and its vascular consequences. Methods Five groups of female mice were used in this study, each one lacking either estrogens (WT-OVX), ERβ (ERβ-KO), ERα (ERα-KO), mem-brane-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), heart rate, vascular structure and reactivity were measured in KO mice and compared to wild-type mice (WT). Results SBP increased from 117±3,05 to 131±2,90 mmHg (ns) in WT mice. A similar increased was observed in C451A mice (124±7,18 vs 103±5,59 mmHg, ns). By contrast, SBP increased significantly more in WT-OVX mice (144±4,97 vs 113±3,17 mmHg, p=0,0007), ERα-KO (155±4,02 mmHg vs 110±2,36 mmHg, p Conclusions Consistently with the literature, we found that estrogens through ERa activation and not ERβ are protective against angiotensin II-induced hypertension. Interestingly, mice deficient in ligand dependent-tran-scriptional-function also developed hypertension whereas mice lacking membrane ERα did not. Taken together, these date 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.