Endothelial Estrogen Receptor-α Does Not Protect Against Vascular Stiffness Induced by Western Diet in Female Mice

Consumption of a diet high in fat and refined carbohydrates (Western diet [WD]) is associated with obesity and insulin resistance, both major risk factors for cardiovascular disease (CVD). In women, obesity and insulin resistance abrogate the protection against CVD likely afforded by estrogen signaling through estrogen receptor (ER)alpha. Indeed, WD in females results in increased vascular stiffness, which is independently associated with CVD. We tested the hypothesis that loss of ER alpha signaling in the endothelium exacerbates WD-induced vascular stiffening in female mice. We used a novel model of endothelial cell (EC)-specific ER alpha knockout (EC-ER alpha KO), obtained after sequential crossing of the ER alpha double floxed mice and VE-Cadherin Cre-recombinase mice. Ten-week-old females, EC-ER alpha KO and aged-matched genopairs were fed either a regular chow diet (control diet) or WD for 8 weeks. Vascular stiffness was measured in vivo by pulse wave velocity and ex vivo in aortic explants by atomic force microscopy. In addition, vascular reactivity was assessed in isolated aortic rings. Initial characterization of the model fed a control diet did not reveal changes in whole-body insulin sensitivity, aortic vasoreactivity, or vascular stiffness in the EC-ER alpha KO mice. Interestingly, ablation of ER alpha in ECs reduced WD-induced vascular stiffness and improved endothelial-dependent dilation. In the setting of a WD, endothelial ER alpha signaling contributes to vascular stiffening in females. The precise mechanisms underlying the detrimental effects of endothelial ER alpha in the setting of a WD remain to be elucidated.