title: Endothelial Mineralocorticoid Receptor Mediates Diet-Induced Aortic Stiffness in Females.
abstract: BACKGROUND
  Enhanced activation of the mineralocorticoid receptors (MRs) in cardiovascular tissues increases oxidative stress, maladaptive immune responses, and inflammation with associated functional vascular abnormalities. We previously demonstrated that consumption of a Western diet (WD) for 16 weeks results in aortic stiffening, and that these abnormalities were prevented by systemic MR blockade in female mice. However, the cell-specific role of endothelial cell MR (ECMR) in these maladaptive vascular effects has not been explored.
  
  
  OBJECTIVE
  We hypothesized that specific deletion of the ECMR would prevent WD-induced increases in endothelial sodium channel activation, reductions in bioavailable nitric oxide, increased vascular remodeling, and associated increases in vascular stiffness in females.
  
  
  RESULTS
  Four-week-old female ECMR knockout and wild-type mice were fed either mouse chow or WD for 16 weeks. WD feeding resulted in aortic stiffness and endothelial dysfunction as determined in vivo by pulse wave velocity and ex vivo by atomic force microscopy, and wire and pressure myography. The WD-induced aortic stiffness was associated with enhanced endothelial sodium channel activation, attenuated endothelial nitric oxide synthase activation, increased oxidative stress, a proinflammatory immune response and fibrosis. Conversely, cell-specific ECMR deficiency prevented WD-induced aortic fibrosis and stiffness in conjunction with reductions in endothelial sodium channel activation, oxidative stress and macrophage proinflammatory polarization, restoration of endothelial nitric oxide synthase activation.
  
  
  CONCLUSIONS
  Increased ECMR signaling associated with consumption of a WD plays a key role in endothelial sodium channel activation, reduced nitric oxide production, oxidative stress, and inflammation that lead to aortic remodeling and stiffness in female mice.
authors.affiliation: Diabetes and Cardiovascular Research Center, University of Missouri School of Medicine, Columbia, MO, 65212, USA.|Research Service, Harry S Truman Memorial Veterans Hospital, Research Service, 800 Hospital Dr, Columbia, MO, 65201, USA.
authors.forename: Guanghong
authors.initials: G
authors.lastname: Jia
authors.affiliation: Diabetes and Cardiovascular Research Center, University of Missouri School of Medicine, Columbia, MO, 65212, USA.|Research Service, Harry S Truman Memorial Veterans Hospital, Research Service, 800 Hospital Dr, Columbia, MO, 65201, USA.
authors.forename: Javad
authors.initials: J
authors.lastname: Habibi
authors.affiliation: Diabetes and Cardiovascular Research Center, University of Missouri School of Medicine, Columbia, MO, 65212, USA.|Research Service, Harry S Truman Memorial Veterans Hospital, Research Service, 800 Hospital Dr, Columbia, MO, 65201, USA.
authors.forename: Annayya R
authors.initials: AR
authors.lastname: Aroor
authors.affiliation: Research Service, Harry S Truman Memorial Veterans Hospital, Research Service, 800 Hospital Dr, Columbia, MO, 65201, USA.|Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, 65212, USA.|Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, 65212, USA.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Martinez-Lemus
authors.affiliation: Diabetes and Cardiovascular Research Center, University of Missouri School of Medicine, Columbia, MO, 65212, USA.|Research Service, Harry S Truman Memorial Veterans Hospital, Research Service, 800 Hospital Dr, Columbia, MO, 65201, USA.|Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, 65212, USA.
authors.forename: Vincent G
authors.initials: VG
authors.lastname: DeMarco
authors.affiliation: Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, 65212, USA.
authors.forename: Francisco I
authors.initials: FI
authors.lastname: Ramirez-Perez
authors.affiliation: Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, 65212, USA.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Diabetes and Cardiovascular Research Center, University of Missouri School of Medicine, Columbia, MO, 65212, USA.|Research Service, Harry S Truman Memorial Veterans Hospital, Research Service, 800 Hospital Dr, Columbia, MO, 65201, USA.
authors.forename: Melvin R
authors.initials: MR
authors.lastname: Hayden
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, 65212, USA.|Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, 65212, USA.
authors.forename: Gerald A
authors.initials: GA
authors.lastname: Meininger
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
authors.forename: Katelee Barrett
authors.initials: KB
authors.lastname: Mueller
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
authors.forename: Iris Z
authors.initials: IZ
authors.lastname: Jaffe
authors.affiliation: Diabetes and Cardiovascular Research Center, University of Missouri School of Medicine, Columbia, MO, 65212, USA.|Research Service, Harry S Truman Memorial Veterans Hospital, Research Service, 800 Hospital Dr, Columbia, MO, 65201, USA.|Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, 65212, USA.|Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, 65212, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology / Q000502:physiology*; D066273:Diet, Western / Q000009:adverse effects*; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D018161:Receptors, Mineralocorticoid / Q000502:physiology*; D059289:Vascular Stiffness / Q000502:physiology*
chemical_list: D018161:Receptors, Mineralocorticoid
keywords: Western diet; inflammation; macrophages; nitric oxide; vascular stiffness