title: Vasodilator-stimulated phosphoprotein protects against vascular inflammation and insulin resistance.
abstract: Among the pleotropic effects of endothelial nitric oxide (NO) is protection against vascular inflammation during high-fat diet (HFD) feeding. The current work investigated the role of the enzyme vasodilatory-stimulated phosphoprotein (VASP) as a downstream mediator of the anti-inflammatory effect of NO signaling in vascular tissue. Relative to mice fed a low-fat diet (LFD), levels of VASP Ser(239) phosphorylation, a marker of VASP activation, were dramatically reduced in aortic tissue of mice with obesity induced by consuming a HFD. As reported previously, the effect of the HFD was associated with increased aortic inflammation, as measured by increased NF-κB-dependent gene expression, and reduced vascular insulin sensitivity (including insulin-stimulated phosphorylation of eNOS and Akt). These effects of the HFD were recapitulated by VASP knockout, implying a physiological role for VASP to constrain inflammatory signaling and thereby maintain vascular insulin sensitivity. Conversely, overexpression of VASP in endothelial cells blocked inflammation and insulin resistance induced by palmitate. The finding that transplantation of bone marrow from VASP-deficient donors into normal recipients does not recapitulate the vascular effects of whole body VASP deficiency suggests that the protective effects of this enzyme are not mediated in immune or other bone marrow-derived cells. These studies implicate VASP as a downstream mediator of the NO/cGMP pathway that is both necessary and sufficient to protect against vascular inflammation and insulin resistance. As such, this work identifies VASP as a potential therapeutic target in the treatment of obesity-related vascular dysfunction.
authors.affiliation: Department of Medicine, Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Cheng
authors.affiliation: Department of Medicine, Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington.
authors.forename: Norma
authors.initials: N
authors.lastname: Rizzo-DeLeon
authors.affiliation: Department of Pathology.
authors.forename: Carole L
authors.initials: CL
authors.lastname: Wilson
authors.affiliation: Department of Medicine, Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington.
authors.forename: Woo Je
authors.initials: WJ
authors.lastname: Lee
authors.affiliation: Department of Medicine, Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington.
authors.forename: Sanshiro
authors.initials: S
authors.lastname: Tateya
authors.affiliation: Department of Surgery, and.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Clowes
authors.affiliation: Department of Medicine, Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Schwartz
authors.affiliation: Department of Medicine, Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington fkim@u.washington.edu.
authors.forename: Francis
authors.initials: F
authors.lastname: Kim
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002417:Cattle; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D059305:Diet, High-Fat; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007333:Insulin Resistance / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D055806:Microvessels / Q000166:cytology; D009569:Nitric Oxide / Q000276:immunology / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D009765:Obesity / Q000276:immunology / Q000378:metabolism*; D010168:Palmitates / Q000494:pharmacology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014657:Vasculitis / Q000276:immunology / Q000378:metabolism*; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010168:Palmitates; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III
keywords: nitric oxide; vascular inflammation; vasodilatory-stimulated phosphoprotein