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

Author:

Manrique Camila1,Lastra Guido1,Ramirez-Perez Francisco I.234,Haertling Dominic1,DeMarco Vincent G.12,Aroor Annayya R.1,Jia Guanghong1,Chen Dongqing1,Barron Brady J.1,Garro Mona1,Padilla Jaume356,Martinez-Lemus Luis A.234,Sowers James R.17

Affiliation:

1. Division of Endocrinology, Diabetes and Metabolism (V.G.D., G.L., G.J., A.R.A., C.M., J.R.S., D.H., D.C., B.J.B., M.G.), Department of Medicine, University of Missouri Columbia School of Medicine, Columbia, Missouri 65212

2. Department of Medical Pharmacology and Physiology (65212) (V.G.D., F.I.R.-P., L.A.M.-L., J.R.S.) Columbia, Missouri 65201

3. Dalton Cardiovascular Research Center (F.I.R.-P., L.A.M.-L., J.P.), University of Missouri, Columbia, Missouri 65201

4. Biological Engineering (L.A.M.-L., F.I.R.-P.), University of Missouri, Columbia, Missouri 65211

5. Department of Nutrition and Exercise Physiology (J.P.), University of Missouri, Columbia, Missouri 65211

6. Departments of Child Health (65201) (J.P.) Columbia, Missouri 65211

7. and Research Service (V.G.D., J.R.S.), Harry S Truman Memorial Veterans Hospital, Columbia, Missouri 65201

Abstract

Abstract 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)α. Indeed, WD in females results in increased vascular stiffness, which is independently associated with CVD. We tested the hypothesis that loss of ERα signaling in the endothelium exacerbates WD-induced vascular stiffening in female mice. We used a novel model of endothelial cell (EC)-specific ERα knockout (EC-ERαKO), obtained after sequential crossing of the ERα double floxed mice and VE-Cadherin Cre-recombinase mice. Ten-week-old females, EC-ERαKO 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-ERαKO mice. Interestingly, ablation of ERα in ECs reduced WD-induced vascular stiffness and improved endothelial-dependent dilation. In the setting of a WD, endothelial ERα signaling contributes to vascular stiffening in females. The precise mechanisms underlying the detrimental effects of endothelial ERα in the setting of a WD remain to be elucidated.

Publisher

The Endocrine Society

Subject

Endocrinology

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