title: Uncoupling of Endothelial Nitric Oxide Synthase in Perivascular Adipose Tissue of Diet-Induced Obese Mice.
abstract: OBJECTIVE
  The present study was conducted to investigate the contribution of perivascular adipose tissue (PVAT) to vascular dysfunction in a mouse model of diet-induced obesity.
  
  
  RESULTS
  Obesity was induced in male C57BL/6J mice with a high-fat diet for 20 weeks, and vascular function was studied with myograph. In PVAT-free aortas isolated from obese mice, the endothelium-dependent, nitric oxide-mediated vasodilator response to acetylcholine remained normal. In contrast, a clear reduction in the vasodilator response to acetylcholine was observed in aortas from obese mice when PVAT was left in place. Adipocytes in PVAT were clearly positive in endothelial nitric oxide synthase (eNOS) staining, and PVAT nitric oxide production was significantly reduced in obese mice. High-fat diet had no effect on eNOS expression but led to eNOS uncoupling, evidenced by diminished superoxide production in PVAT after eNOS inhibition. As mechanisms for eNOS uncoupling, arginase induction and l-arginine deficiency were observed in PVAT. Obesity-induced vascular dysfunction could be reversed by ex vivo l-arginine treatment and arginase inhibition.
  
  
  CONCLUSIONS
  Diet-induced obesity leads to l-arginine deficiency and eNOS uncoupling in PVAT. The combination therapy with l-arginine and arginase inhibitors may represent a novel therapeutic strategy for obesity-induced vascular disease.
authors.affiliation: From the Department of Pharmacology (N.X., S.H., A.H., E.I.C., G.R., U.F., H.L.), Center for Thrombosis and Hemostasis (S.H.), Department of Ophthalmology (A.G.), and Second Medical Department, Cardiology and Angiology (Y.M., T.M., A.D.), Johannes Gutenberg University Medical Center, Mainz, Germany; and German Center for Cardiovascular Research (DZHK), partner site Rhine-Main, Mainz, Germany (T.M., A.D., H.L.).
authors.forename: Ning
authors.initials: N
authors.lastname: Xia
authors.affiliation: From the Department of Pharmacology (N.X., S.H., A.H., E.I.C., G.R., U.F., H.L.), Center for Thrombosis and Hemostasis (S.H.), Department of Ophthalmology (A.G.), and Second Medical Department, Cardiology and Angiology (Y.M., T.M., A.D.), Johannes Gutenberg University Medical Center, Mainz, Germany; and German Center for Cardiovascular Research (DZHK), partner site Rhine-Main, Mainz, Germany (T.M., A.D., H.L.).
authors.forename: Sven
authors.initials: S
authors.lastname: Horke
authors.affiliation: From the Department of Pharmacology (N.X., S.H., A.H., E.I.C., G.R., U.F., H.L.), Center for Thrombosis and Hemostasis (S.H.), Department of Ophthalmology (A.G.), and Second Medical Department, Cardiology and Angiology (Y.M., T.M., A.D.), Johannes Gutenberg University Medical Center, Mainz, Germany; and German Center for Cardiovascular Research (DZHK), partner site Rhine-Main, Mainz, Germany (T.M., A.D., H.L.).
authors.forename: Alice
authors.initials: A
authors.lastname: Habermeier
authors.affiliation: From the Department of Pharmacology (N.X., S.H., A.H., E.I.C., G.R., U.F., H.L.), Center for Thrombosis and Hemostasis (S.H.), Department of Ophthalmology (A.G.), and Second Medical Department, Cardiology and Angiology (Y.M., T.M., A.D.), Johannes Gutenberg University Medical Center, Mainz, Germany; and German Center for Cardiovascular Research (DZHK), partner site Rhine-Main, Mainz, Germany (T.M., A.D., H.L.).
authors.forename: Ellen I
authors.initials: EI
authors.lastname: Closs
authors.affiliation: From the Department of Pharmacology (N.X., S.H., A.H., E.I.C., G.R., U.F., H.L.), Center for Thrombosis and Hemostasis (S.H.), Department of Ophthalmology (A.G.), and Second Medical Department, Cardiology and Angiology (Y.M., T.M., A.D.), Johannes Gutenberg University Medical Center, Mainz, Germany; and German Center for Cardiovascular Research (DZHK), partner site Rhine-Main, Mainz, Germany (T.M., A.D., H.L.).
authors.forename: Gisela
authors.initials: G
authors.lastname: Reifenberg
authors.affiliation: From the Department of Pharmacology (N.X., S.H., A.H., E.I.C., G.R., U.F., H.L.), Center for Thrombosis and Hemostasis (S.H.), Department of Ophthalmology (A.G.), and Second Medical Department, Cardiology and Angiology (Y.M., T.M., A.D.), Johannes Gutenberg University Medical Center, Mainz, Germany; and German Center for Cardiovascular Research (DZHK), partner site Rhine-Main, Mainz, Germany (T.M., A.D., H.L.).
authors.forename: Adrian
authors.initials: A
authors.lastname: Gericke
authors.affiliation: From the Department of Pharmacology (N.X., S.H., A.H., E.I.C., G.R., U.F., H.L.), Center for Thrombosis and Hemostasis (S.H.), Department of Ophthalmology (A.G.), and Second Medical Department, Cardiology and Angiology (Y.M., T.M., A.D.), Johannes Gutenberg University Medical Center, Mainz, Germany; and German Center for Cardiovascular Research (DZHK), partner site Rhine-Main, Mainz, Germany (T.M., A.D., H.L.).
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Mikhed
authors.affiliation: From the Department of Pharmacology (N.X., S.H., A.H., E.I.C., G.R., U.F., H.L.), Center for Thrombosis and Hemostasis (S.H.), Department of Ophthalmology (A.G.), and Second Medical Department, Cardiology and Angiology (Y.M., T.M., A.D.), Johannes Gutenberg University Medical Center, Mainz, Germany; and German Center for Cardiovascular Research (DZHK), partner site Rhine-Main, Mainz, Germany (T.M., A.D., H.L.).
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.affiliation: From the Department of Pharmacology (N.X., S.H., A.H., E.I.C., G.R., U.F., H.L.), Center for Thrombosis and Hemostasis (S.H.), Department of Ophthalmology (A.G.), and Second Medical Department, Cardiology and Angiology (Y.M., T.M., A.D.), Johannes Gutenberg University Medical Center, Mainz, Germany; and German Center for Cardiovascular Research (DZHK), partner site Rhine-Main, Mainz, Germany (T.M., A.D., H.L.).
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
authors.affiliation: From the Department of Pharmacology (N.X., S.H., A.H., E.I.C., G.R., U.F., H.L.), Center for Thrombosis and Hemostasis (S.H.), Department of Ophthalmology (A.G.), and Second Medical Department, Cardiology and Angiology (Y.M., T.M., A.D.), Johannes Gutenberg University Medical Center, Mainz, Germany; and German Center for Cardiovascular Research (DZHK), partner site Rhine-Main, Mainz, Germany (T.M., A.D., H.L.).
authors.forename: Ulrich
authors.initials: U
authors.lastname: Förstermann
authors.affiliation: From the Department of Pharmacology (N.X., S.H., A.H., E.I.C., G.R., U.F., H.L.), Center for Thrombosis and Hemostasis (S.H.), Department of Ophthalmology (A.G.), and Second Medical Department, Cardiology and Angiology (Y.M., T.M., A.D.), Johannes Gutenberg University Medical Center, Mainz, Germany; and German Center for Cardiovascular Research (DZHK), partner site Rhine-Main, Mainz, Germany (T.M., A.D., H.L.). huigeli@uni-mainz.de.
authors.forename: Huige
authors.initials: H
authors.lastname: Li
mesh_terms: D017667:Adipocytes / Q000201:enzymology; D054392:Adipokines / Q000378:metabolism; D000273:Adipose Tissue / Q000201:enzymology* / Q000503:physiopathology; D050154:Adiposity; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D001119:Arginase / Q000037:antagonists & inhibitors / Q000378:metabolism; D001120:Arginine / Q000172:deficiency; D016207:Cytokines / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009765:Obesity / Q000201:enzymology* / Q000503:physiopathology; D019899:Paracrine Communication; D010766:Phosphorylation; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D054392:Adipokines; D016207:Cytokines; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D014665:Vasodilator Agents; D013481:Superoxides; D009569:Nitric Oxide; D001120:Arginine; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D001119:Arginase
keywords: eNOS uncoupling; nitric oxide; obesity; perivascular adipose tissue; vascular function