title: Antiangiogenic actions of vascular endothelial growth factor-A165b, an inhibitory isoform of vascular endothelial growth factor-A, in human obesity.
abstract: BACKGROUND
  Experimental studies suggest that visceral adiposity and adipose tissue dysfunction play a central role in obesity-related cardiometabolic complications. Impaired angiogenesis in fat has been implicated in the development of adipose tissue hypoxia, capillary rarefaction, inflammation, and metabolic dysregulation, but pathophysiological mechanisms remain unknown. In this study, we examined the role of a novel antiangiogenic isoform of vascular endothelial growth factor-A (VEGF-A), VEGF-A165b, in human obesity.
  
  
  RESULTS
  We biopsied paired subcutaneous and visceral adipose tissue in 40 obese subjects (body mass index, 45±8 kg/m(2); age, 45±11 years) during bariatric surgery and characterized depot-specific adipose tissue angiogenic capacity using an established ex vivo assay. Visceral adipose tissue exhibited significantly blunted angiogenic growth compared with subcutaneous fat (P<0.001) that was associated with marked tissue upregulation of VEGF-A165b (P=0.004). The extent of VEGF-A165b expression correlated negatively with angiogenic growth (r=-0.6, P=0.006). Although recombinant VEGF-A165b significantly impaired angiogenesis, targeted inhibition of VEGF-A165b with neutralizing antibody stimulated fat pad neovascularization and restored VEGF receptor activation. Blood levels of VEGF-A165b were significantly higher in obese subjects compared with lean control subjects (P=0.02), and surgical weight loss induced a marked decline in serumVEGF-A165b (P=0.003).
  
  
  CONCLUSIONS
  We demonstrate that impaired adipose tissue angiogenesis is associated with overexpression of a novel antiangiogenic factor, VEGF-A165b, that may play a pathogenic role in human adiposopathy. Moreover, systemic upregulation of VEGF-A165b in circulating blood may have wider-ranging implications beyond the adipose milieu. VEGF-A165b may represent a novel area of investigation to gain further understanding of mechanisms that modulate the cardiometabolic consequences of obesity.
authors.affiliation: From the Evans Department of Medicine and Whitaker Cardiovascular Institute (D.T.M.N., M.G.F., R.K., S.K., S.T., S.J.B., N.M.H., J.A.V., K.W., N.G.) and Department of General Surgery (D.T.H.), Boston University School of Medicine, Boston, MA; Microvascular Research Laboratories, School of Physiology and Pharmacology, Bristol Heart Institute, School of Veterinary Science, University of Bristol, Bristol, UK (D.O.B.); and Department of Biostatistics, Boston University School of Public Health, Boston, MA (M.P.L.).
authors.forename: Doan T M
authors.initials: DT
authors.lastname: Ngo
authors.affiliation: From the Evans Department of Medicine and Whitaker Cardiovascular Institute (D.T.M.N., M.G.F., R.K., S.K., S.T., S.J.B., N.M.H., J.A.V., K.W., N.G.) and Department of General Surgery (D.T.H.), Boston University School of Medicine, Boston, MA; Microvascular Research Laboratories, School of Physiology and Pharmacology, Bristol Heart Institute, School of Veterinary Science, University of Bristol, Bristol, UK (D.O.B.); and Department of Biostatistics, Boston University School of Public Health, Boston, MA (M.P.L.).
authors.forename: Melissa G
authors.initials: MG
authors.lastname: Farb
authors.affiliation: From the Evans Department of Medicine and Whitaker Cardiovascular Institute (D.T.M.N., M.G.F., R.K., S.K., S.T., S.J.B., N.M.H., J.A.V., K.W., N.G.) and Department of General Surgery (D.T.H.), Boston University School of Medicine, Boston, MA; Microvascular Research Laboratories, School of Physiology and Pharmacology, Bristol Heart Institute, School of Veterinary Science, University of Bristol, Bristol, UK (D.O.B.); and Department of Biostatistics, Boston University School of Public Health, Boston, MA (M.P.L.).
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kikuchi
authors.affiliation: From the Evans Department of Medicine and Whitaker Cardiovascular Institute (D.T.M.N., M.G.F., R.K., S.K., S.T., S.J.B., N.M.H., J.A.V., K.W., N.G.) and Department of General Surgery (D.T.H.), Boston University School of Medicine, Boston, MA; Microvascular Research Laboratories, School of Physiology and Pharmacology, Bristol Heart Institute, School of Veterinary Science, University of Bristol, Bristol, UK (D.O.B.); and Department of Biostatistics, Boston University School of Public Health, Boston, MA (M.P.L.).
authors.forename: Shakun
authors.initials: S
authors.lastname: Karki
authors.affiliation: From the Evans Department of Medicine and Whitaker Cardiovascular Institute (D.T.M.N., M.G.F., R.K., S.K., S.T., S.J.B., N.M.H., J.A.V., K.W., N.G.) and Department of General Surgery (D.T.H.), Boston University School of Medicine, Boston, MA; Microvascular Research Laboratories, School of Physiology and Pharmacology, Bristol Heart Institute, School of Veterinary Science, University of Bristol, Bristol, UK (D.O.B.); and Department of Biostatistics, Boston University School of Public Health, Boston, MA (M.P.L.).
authors.forename: Stephanie
authors.initials: S
authors.lastname: Tiwari
authors.affiliation: From the Evans Department of Medicine and Whitaker Cardiovascular Institute (D.T.M.N., M.G.F., R.K., S.K., S.T., S.J.B., N.M.H., J.A.V., K.W., N.G.) and Department of General Surgery (D.T.H.), Boston University School of Medicine, Boston, MA; Microvascular Research Laboratories, School of Physiology and Pharmacology, Bristol Heart Institute, School of Veterinary Science, University of Bristol, Bristol, UK (D.O.B.); and Department of Biostatistics, Boston University School of Public Health, Boston, MA (M.P.L.).
authors.forename: Sherman J
authors.initials: SJ
authors.lastname: Bigornia
authors.affiliation: From the Evans Department of Medicine and Whitaker Cardiovascular Institute (D.T.M.N., M.G.F., R.K., S.K., S.T., S.J.B., N.M.H., J.A.V., K.W., N.G.) and Department of General Surgery (D.T.H.), Boston University School of Medicine, Boston, MA; Microvascular Research Laboratories, School of Physiology and Pharmacology, Bristol Heart Institute, School of Veterinary Science, University of Bristol, Bristol, UK (D.O.B.); and Department of Biostatistics, Boston University School of Public Health, Boston, MA (M.P.L.).
authors.forename: David O
authors.initials: DO
authors.lastname: Bates
authors.affiliation: From the Evans Department of Medicine and Whitaker Cardiovascular Institute (D.T.M.N., M.G.F., R.K., S.K., S.T., S.J.B., N.M.H., J.A.V., K.W., N.G.) and Department of General Surgery (D.T.H.), Boston University School of Medicine, Boston, MA; Microvascular Research Laboratories, School of Physiology and Pharmacology, Bristol Heart Institute, School of Veterinary Science, University of Bristol, Bristol, UK (D.O.B.); and Department of Biostatistics, Boston University School of Public Health, Boston, MA (M.P.L.).
authors.forename: Michael P
authors.initials: MP
authors.lastname: LaValley
authors.affiliation: From the Evans Department of Medicine and Whitaker Cardiovascular Institute (D.T.M.N., M.G.F., R.K., S.K., S.T., S.J.B., N.M.H., J.A.V., K.W., N.G.) and Department of General Surgery (D.T.H.), Boston University School of Medicine, Boston, MA; Microvascular Research Laboratories, School of Physiology and Pharmacology, Bristol Heart Institute, School of Veterinary Science, University of Bristol, Bristol, UK (D.O.B.); and Department of Biostatistics, Boston University School of Public Health, Boston, MA (M.P.L.).
authors.forename: Naomi M
authors.initials: NM
authors.lastname: Hamburg
authors.affiliation: From the Evans Department of Medicine and Whitaker Cardiovascular Institute (D.T.M.N., M.G.F., R.K., S.K., S.T., S.J.B., N.M.H., J.A.V., K.W., N.G.) and Department of General Surgery (D.T.H.), Boston University School of Medicine, Boston, MA; Microvascular Research Laboratories, School of Physiology and Pharmacology, Bristol Heart Institute, School of Veterinary Science, University of Bristol, Bristol, UK (D.O.B.); and Department of Biostatistics, Boston University School of Public Health, Boston, MA (M.P.L.).
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Vita
authors.affiliation: From the Evans Department of Medicine and Whitaker Cardiovascular Institute (D.T.M.N., M.G.F., R.K., S.K., S.T., S.J.B., N.M.H., J.A.V., K.W., N.G.) and Department of General Surgery (D.T.H.), Boston University School of Medicine, Boston, MA; Microvascular Research Laboratories, School of Physiology and Pharmacology, Bristol Heart Institute, School of Veterinary Science, University of Bristol, Bristol, UK (D.O.B.); and Department of Biostatistics, Boston University School of Public Health, Boston, MA (M.P.L.).
authors.forename: Donald T
authors.initials: DT
authors.lastname: Hess
authors.affiliation: From the Evans Department of Medicine and Whitaker Cardiovascular Institute (D.T.M.N., M.G.F., R.K., S.K., S.T., S.J.B., N.M.H., J.A.V., K.W., N.G.) and Department of General Surgery (D.T.H.), Boston University School of Medicine, Boston, MA; Microvascular Research Laboratories, School of Physiology and Pharmacology, Bristol Heart Institute, School of Veterinary Science, University of Bristol, Bristol, UK (D.O.B.); and Department of Biostatistics, Boston University School of Public Health, Boston, MA (M.P.L.).
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.affiliation: From the Evans Department of Medicine and Whitaker Cardiovascular Institute (D.T.M.N., M.G.F., R.K., S.K., S.T., S.J.B., N.M.H., J.A.V., K.W., N.G.) and Department of General Surgery (D.T.H.), Boston University School of Medicine, Boston, MA; Microvascular Research Laboratories, School of Physiology and Pharmacology, Bristol Heart Institute, School of Veterinary Science, University of Bristol, Bristol, UK (D.O.B.); and Department of Biostatistics, Boston University School of Public Health, Boston, MA (M.P.L.). Noyan.Gokce@bmc.org.
authors.forename: Noyan
authors.initials: N
authors.lastname: Gokce
mesh_terms: D000328:Adult; D020533:Angiogenesis Inhibitors / Q000502:physiology*; D001706:Biopsy; D005260:Female; D006801:Humans; D050152:Intra-Abdominal Fat / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000473:pathology / Q000503:physiopathology*; D020033:Protein Isoforms / Q000502:physiology; D012189:Retrospective Studies; D015398:Signal Transduction / Q000502:physiology; D050151:Subcutaneous Fat / Q000473:pathology / Q000503:physiopathology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology
chemical_list: D020533:Angiogenesis Inhibitors; D020033:Protein Isoforms; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: angiogenesis modulating agents; intra-abdominal fat; metabolism; obesity; vascular endothelial growth factor A; vascular endothelial growth factors