0188 : Molecular mechanisms involved in the vascular protection induced by estrogen receptor alpha during hypertension in the mouse

Women, before menopause, are less affected than men by hypertension and atherosclerosis, the main causes of cardiovascular diseases. Estrogens have been shown to protect the vascular endothelium through their nuclear receptors, mainly via the 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 play a protective role in endothelial cells but their respective role in hypertension is unknown. To investigate the protective effects of ERα in hypertension, we used (i) mice lacking ERα (ERα-/-), (ii) mice with a point mutation of the palmitoylation site of ERα (C451A-ERα) to obtain membrane-specific loss of function (iii) mice lacking the AF2 ligand-dependant-transcriptional function domain of ERα (AF2°) and (iv) wild type (WT) mice. Hypertension was induced using Angiotensin II (Alzet minipumps) and blood pressure measured using tail cuff. After 28 days vascular structure and function were measured in vitro. Angiotensin II-induced hypertension was greater in ERα-/- and in AF2° mice than in WT and C451AERα mice. These data suggest that the protective effect of ERα against elevated blood pressure involved nuclear AF2-mediated transcriptional functions rather than MISS-mediated function. Changes in pressure were associated with proportional changes in endothelium-dependent dilation and wall thickness. Thanks to this work, we hope to better understand how ERα is able to mediate the protective effects of estrogen against hypertension.