Endothelial Estrogen Receptor Beta Deletion Augments Endothelial Function in High Fat Diet Fed-Female Mice

Arterial stiffening and endothelial dysfunction are key contributors to the development and progression of cardiovascular disease (CVD) in women with obesity. Estrogen actions in the vasculature, mainly mediated via estrogen receptor alpha (ERα), result in enhanced endothelial function, lowered arterial stiffness and decreased blood pressure. However, these vasculoprotective effects seem to be abrogated in obesity. The role that estrogen receptor beta (ERβ) plays in maintaining vascular health in females is not well-characterized and previous studies have pointed toward an inhibitory effect of ERβ signaling on the ERα mediated vascular relaxation. Therefore, the present investigation is aimed at examining the role of endothelial cell (EC) ERβ on endothelial function and arterial stiffness in a model of obesity. EC-ERβKO female mice (ERβ double floxed VE cadherin-Cre+) and their respective littermates (ERβ double floxed Cre-) were fed control chow or a high fat diet (60%) starting at 12 weeks of age for 16 weeks. All reported differences are significant at p<0.05. HFD feeding resulted in significant weight gain in the EC-ERβKO and control groups. Neither, HFD nor EC ERβ deletion impacted blood pressure. As expected, HFD feeding resulted in aortic stiffening in the control cohort. Conversely, ERβ deletion in EC tended (P=0.06) to ameliorate aortic stiffening associated with HFD feeding. After euthanasia and using pressure myography, we also determined ex vivo mesenteric artery vasomotor function and stiffness by measuring flow-mediated dilation (FMD), vascular responses to insulin (INS), sodium nitroprusside (SNP), and the passive mechanical properties of the arterial wall, respectively. Sixteen weeks of HFD resulted in blunted FMD responses only in the control cohort. INS-induced vasodilation was enhanced in the EC-ERβKO group fed HFD. Vasomotor responses to SNP (i.e. endothelial independent) were similar among groups. Contrary to our findings in the aorta, EC ERβ deletion resulted in increased incremental modulus of elasticity (increased stiffness) in mesenteric arteries. Collectively, these findings suggest that deletion of EC ERβ in the setting of obesity enhances endothelial vasodilatory function with a variable impact on arterial stiffening that is dependent on the vascular bed examined. Further studies are needed to delineate the interactions between ERβ and ERα in the endothelium, and their impact in the pathogenesis of CVD in women with obesity and insulin resistance. Funding supported by R01 HL142770 (CM-A). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.