title: Endothelial Estrogen Receptor-α Does Not Protect Against Vascular Stiffness Induced by Western Diet in Female Mice.
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.
authors.affiliation: 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; Department of Medical Pharmacology and Physiology (65212) (V.G.D., F.I.R.-P., L.A.M.-L., J.R.S.) and Research Service (V.G.D., J.R.S.), Harry S Truman Memorial Veterans Hospital, Columbia, Missouri 65201; Dalton Cardiovascular Research Center (F.I.R.-P., L.A.M.-L., J.P.), University of Missouri, Columbia, Missouri 65201; Department of Nutrition and Exercise Physiology (J.P.), University of Missouri, Columbia, Missouri 65211; and Departments of Child Health (65201) (J.P.) and Biological Engineering (L.A.M.-L., F.I.R.-P.), University of Missouri, Columbia, Missouri 65211.
authors.forename: Camila
authors.initials: C
authors.lastname: Manrique
authors.affiliation: 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; Department of Medical Pharmacology and Physiology (65212) (V.G.D., F.I.R.-P., L.A.M.-L., J.R.S.) and Research Service (V.G.D., J.R.S.), Harry S Truman Memorial Veterans Hospital, Columbia, Missouri 65201; Dalton Cardiovascular Research Center (F.I.R.-P., L.A.M.-L., J.P.), University of Missouri, Columbia, Missouri 65201; Department of Nutrition and Exercise Physiology (J.P.), University of Missouri, Columbia, Missouri 65211; and Departments of Child Health (65201) (J.P.) and Biological Engineering (L.A.M.-L., F.I.R.-P.), University of Missouri, Columbia, Missouri 65211.
authors.forename: Guido
authors.initials: G
authors.lastname: Lastra
authors.affiliation: 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; Department of Medical Pharmacology and Physiology (65212) (V.G.D., F.I.R.-P., L.A.M.-L., J.R.S.) and Research Service (V.G.D., J.R.S.), Harry S Truman Memorial Veterans Hospital, Columbia, Missouri 65201; Dalton Cardiovascular Research Center (F.I.R.-P., L.A.M.-L., J.P.), University of Missouri, Columbia, Missouri 65201; Department of Nutrition and Exercise Physiology (J.P.), University of Missouri, Columbia, Missouri 65211; and Departments of Child Health (65201) (J.P.) and Biological Engineering (L.A.M.-L., F.I.R.-P.), University of Missouri, Columbia, Missouri 65211.
authors.forename: Francisco I
authors.initials: FI
authors.lastname: Ramirez-Perez
authors.affiliation: 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; Department of Medical Pharmacology and Physiology (65212) (V.G.D., F.I.R.-P., L.A.M.-L., J.R.S.) and Research Service (V.G.D., J.R.S.), Harry S Truman Memorial Veterans Hospital, Columbia, Missouri 65201; Dalton Cardiovascular Research Center (F.I.R.-P., L.A.M.-L., J.P.), University of Missouri, Columbia, Missouri 65201; Department of Nutrition and Exercise Physiology (J.P.), University of Missouri, Columbia, Missouri 65211; and Departments of Child Health (65201) (J.P.) and Biological Engineering (L.A.M.-L., F.I.R.-P.), University of Missouri, Columbia, Missouri 65211.
authors.forename: Dominic
authors.initials: D
authors.lastname: Haertling
authors.affiliation: 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; Department of Medical Pharmacology and Physiology (65212) (V.G.D., F.I.R.-P., L.A.M.-L., J.R.S.) and Research Service (V.G.D., J.R.S.), Harry S Truman Memorial Veterans Hospital, Columbia, Missouri 65201; Dalton Cardiovascular Research Center (F.I.R.-P., L.A.M.-L., J.P.), University of Missouri, Columbia, Missouri 65201; Department of Nutrition and Exercise Physiology (J.P.), University of Missouri, Columbia, Missouri 65211; and Departments of Child Health (65201) (J.P.) and Biological Engineering (L.A.M.-L., F.I.R.-P.), University of Missouri, Columbia, Missouri 65211.
authors.forename: Vincent G
authors.initials: VG
authors.lastname: DeMarco
authors.affiliation: 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; Department of Medical Pharmacology and Physiology (65212) (V.G.D., F.I.R.-P., L.A.M.-L., J.R.S.) and Research Service (V.G.D., J.R.S.), Harry S Truman Memorial Veterans Hospital, Columbia, Missouri 65201; Dalton Cardiovascular Research Center (F.I.R.-P., L.A.M.-L., J.P.), University of Missouri, Columbia, Missouri 65201; Department of Nutrition and Exercise Physiology (J.P.), University of Missouri, Columbia, Missouri 65211; and Departments of Child Health (65201) (J.P.) and Biological Engineering (L.A.M.-L., F.I.R.-P.), University of Missouri, Columbia, Missouri 65211.
authors.forename: Annayya R
authors.initials: AR
authors.lastname: Aroor
authors.affiliation: 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; Department of Medical Pharmacology and Physiology (65212) (V.G.D., F.I.R.-P., L.A.M.-L., J.R.S.) and Research Service (V.G.D., J.R.S.), Harry S Truman Memorial Veterans Hospital, Columbia, Missouri 65201; Dalton Cardiovascular Research Center (F.I.R.-P., L.A.M.-L., J.P.), University of Missouri, Columbia, Missouri 65201; Department of Nutrition and Exercise Physiology (J.P.), University of Missouri, Columbia, Missouri 65211; and Departments of Child Health (65201) (J.P.) and Biological Engineering (L.A.M.-L., F.I.R.-P.), University of Missouri, Columbia, Missouri 65211.
authors.forename: Guanghong
authors.initials: G
authors.lastname: Jia
authors.affiliation: 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; Department of Medical Pharmacology and Physiology (65212) (V.G.D., F.I.R.-P., L.A.M.-L., J.R.S.) and Research Service (V.G.D., J.R.S.), Harry S Truman Memorial Veterans Hospital, Columbia, Missouri 65201; Dalton Cardiovascular Research Center (F.I.R.-P., L.A.M.-L., J.P.), University of Missouri, Columbia, Missouri 65201; Department of Nutrition and Exercise Physiology (J.P.), University of Missouri, Columbia, Missouri 65211; and Departments of Child Health (65201) (J.P.) and Biological Engineering (L.A.M.-L., F.I.R.-P.), University of Missouri, Columbia, Missouri 65211.
authors.forename: Dongqing
authors.initials: D
authors.lastname: Chen
authors.affiliation: 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; Department of Medical Pharmacology and Physiology (65212) (V.G.D., F.I.R.-P., L.A.M.-L., J.R.S.) and Research Service (V.G.D., J.R.S.), Harry S Truman Memorial Veterans Hospital, Columbia, Missouri 65201; Dalton Cardiovascular Research Center (F.I.R.-P., L.A.M.-L., J.P.), University of Missouri, Columbia, Missouri 65201; Department of Nutrition and Exercise Physiology (J.P.), University of Missouri, Columbia, Missouri 65211; and Departments of Child Health (65201) (J.P.) and Biological Engineering (L.A.M.-L., F.I.R.-P.), University of Missouri, Columbia, Missouri 65211.
authors.forename: Brady J
authors.initials: BJ
authors.lastname: Barron
authors.affiliation: 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; Department of Medical Pharmacology and Physiology (65212) (V.G.D., F.I.R.-P., L.A.M.-L., J.R.S.) and Research Service (V.G.D., J.R.S.), Harry S Truman Memorial Veterans Hospital, Columbia, Missouri 65201; Dalton Cardiovascular Research Center (F.I.R.-P., L.A.M.-L., J.P.), University of Missouri, Columbia, Missouri 65201; Department of Nutrition and Exercise Physiology (J.P.), University of Missouri, Columbia, Missouri 65211; and Departments of Child Health (65201) (J.P.) and Biological Engineering (L.A.M.-L., F.I.R.-P.), University of Missouri, Columbia, Missouri 65211.
authors.forename: Mona
authors.initials: M
authors.lastname: Garro
authors.affiliation: 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; Department of Medical Pharmacology and Physiology (65212) (V.G.D., F.I.R.-P., L.A.M.-L., J.R.S.) and Research Service (V.G.D., J.R.S.), Harry S Truman Memorial Veterans Hospital, Columbia, Missouri 65201; Dalton Cardiovascular Research Center (F.I.R.-P., L.A.M.-L., J.P.), University of Missouri, Columbia, Missouri 65201; Department of Nutrition and Exercise Physiology (J.P.), University of Missouri, Columbia, Missouri 65211; and Departments of Child Health (65201) (J.P.) and Biological Engineering (L.A.M.-L., F.I.R.-P.), University of Missouri, Columbia, Missouri 65211.
authors.forename: Jaume
authors.initials: J
authors.lastname: Padilla
authors.affiliation: 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; Department of Medical Pharmacology and Physiology (65212) (V.G.D., F.I.R.-P., L.A.M.-L., J.R.S.) and Research Service (V.G.D., J.R.S.), Harry S Truman Memorial Veterans Hospital, Columbia, Missouri 65201; Dalton Cardiovascular Research Center (F.I.R.-P., L.A.M.-L., J.P.), University of Missouri, Columbia, Missouri 65201; Department of Nutrition and Exercise Physiology (J.P.), University of Missouri, Columbia, Missouri 65211; and Departments of Child Health (65201) (J.P.) and Biological Engineering (L.A.M.-L., F.I.R.-P.), University of Missouri, Columbia, Missouri 65211.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Martinez-Lemus
authors.affiliation: 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; Department of Medical Pharmacology and Physiology (65212) (V.G.D., F.I.R.-P., L.A.M.-L., J.R.S.) and Research Service (V.G.D., J.R.S.), Harry S Truman Memorial Veterans Hospital, Columbia, Missouri 65201; Dalton Cardiovascular Research Center (F.I.R.-P., L.A.M.-L., J.P.), University of Missouri, Columbia, Missouri 65201; Department of Nutrition and Exercise Physiology (J.P.), University of Missouri, Columbia, Missouri 65211; and Departments of Child Health (65201) (J.P.) and Biological Engineering (L.A.M.-L., F.I.R.-P.), University of Missouri, Columbia, Missouri 65211.
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001013:Aorta, Thoracic / Q000378:metabolism / Q000502:physiology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D066273:Diet, Western; D042783:Endothelial Cells / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005263:Femoral Artery / Q000502:physiology; D015151:Immunoblotting; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018625:Microscopy, Atomic Force; D063177:Pulse Wave Analysis; D016212:Transforming Growth Factor beta / Q000378:metabolism; D059289:Vascular Stiffness / Q000235:genetics / Q000502:physiology*; D014664:Vasodilation; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D047628:Estrogen Receptor alpha; D016212:Transforming Growth Factor beta; D000099152:Cadherin 5