0329 : Role of the estrogen receptor alpha (ERalpha) in the vascular response to shear stress in mice

Small resistance arteries regulate peripheral tissue perfusion following variations in arterial pressure and blood flow. An alteration of the acute flowmediated dilation (FMD) in response to an elevation in intra-arterial shear stress is the hallmark of early vascular dysfunction and ageing. We recently showed that flow-dependent arterial remodeling, an adaptive phenomenon lost with age, was controlled by the endothelial estrogen receptor alpha (ERα). Our goal was thus to evaluate the role of ERαin endothelial mechano-sensitive mechanisms related to the acute response to flow, by using multiple models of ERαdeficiency in male mice, avoiding the hormonal influence of estrogens encountered in females. The evaluation of the FMD was performed on pressurized mesenteric resistance arteries mounted on an arteriograph following step increase in intraluminal flow (6-100 μl/min). Arteries were isolated from wild-type (WT) and ERαgenetically modified male mice deficient in (i) total ERα(ERαKO), (ii) the ligand-dependent transactivation function AF2 (AF2°) or (iii) the plasmic membrane-located ERαfollowing a point mutation of the palmitoylation site of the receptor (C451A). We first observed a selective alteration of FMD, without any major modification in response to vasodilator agonists (acetylcholine), in male mice deficient in total ERα. Interestingly, while the activation of the AF2 function involved in the nuclear action of ERαseemed only partially involved (% dilation 50μl/min: AF2: 49,5+/-11,8 vs. WT: 68,0+/-7,9 p=ns.), a default in receptor membrane addressing in C451A male mice markedly altered FMD (% dilation 50μl/min: C451A:29,4+/-5,1 vs. WT:59,3+/-10,6 ; p<0,05). We thus show, for the first time, that membrane ERαcontributes to arterial shear-sensing and could be pointed out as a new therapeutical target in peripheral vascular diseases, overcoming the known pro-cancerous action of nuclear ERαstimulation.