title: Increased mitochondrial ROS generation mediates the loss of the anti-contractile effects of perivascular adipose tissue in high-fat diet obese mice.
abstract: OBJECTIVE
  Obesity is associated with structural and functional changes in perivascular adipose tissue (PVAT), favouring release of reactive oxygen species (ROS), vasoconstrictor and proinflammatory factors. The cytokine TNF-α induces vascular dysfunction and is produced by PVAT. We tested the hypothesis that obesity-associated PVAT dysfunction was mediated by augmented mitochondrial ROS (mROS) generation due to increased TNF-α production in this tissue.
  
  
  METHODS
  C57Bl/6J and TNF-α receptor-deficient mice received control or high fat diet (HFD) for 18 weeks. We used pharmacological tools to determine the participation of mROS in PVAT dysfunction. Superoxide anion (O2.-) and H2O2were assayed in PVAT and aortic rings were used to assess vascular function.
  
  
  RESULTS
  Aortae from HFD-fed obese mice displayed increased contractions to phenylephrine and loss of PVAT anti-contractile effect. Inactivation of O2.-, dismutation of mitochondria-derived H2O2, uncoupling of oxidative phosphorylation and Rho kinase inhibition, decreased phenylephrine-induced contractions in aortae with PVAT from HFD-fed mice. O2.-and H2O2were increased in PVAT from HFD-fed mice. Mitochondrial respiration analysis revealed decreased O2consumption rates in PVAT from HFD-fed mice. TNF-α inhibition reduced H2O2levels in PVAT from HFD-fed mice. PVAT dysfunction, i.e. increased contraction to phenylephrine in PVAT-intact aortae, was not observed in HFD-obese mice lacking TNF-α receptors. Generation of H2O2was prevented in PVAT from TNF-α receptor deficient obese mice.
  
  
  CONCLUSIONS
  TNF-α-induced mitochondrial oxidative stress is a key and novel mechanism involved in obesity-associated PVAT dysfunction. These findings elucidate molecular mechanisms whereby oxidative stress in PVAT could affect vascular function.
  
  
  BACKGROUND
  This article is part of a themed section on Molecular Mechanisms Regulating Perivascular Adipose Tissue - Potential Pharmacological Targets? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.20/issuetoc.
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Rafael Menezes
authors.initials: RM
authors.lastname: da Costa
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Rafael S
authors.initials: RS
authors.lastname: Fais
authors.affiliation: Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Carlos R P
authors.initials: CRP
authors.lastname: Dechandt
authors.affiliation: Division of Clinical Immunology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Paulo
authors.initials: P
authors.lastname: Louzada-Junior
authors.affiliation: Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Luciane C
authors.initials: LC
authors.lastname: Alberici
authors.affiliation: Department of Medicine, Federal University of Goias, Jatai, GO, Brazil.
authors.forename: Núbia S
authors.initials: NS
authors.lastname: Lobato
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
authors.forename: Rita C
authors.initials: RC
authors.lastname: Tostes
mesh_terms: D000273:Adipose Tissue / Q000502:physiology*; D000818:Animals; D001013:Aorta, Thoracic / Q000502:physiology*; D059305:Diet, High-Fat; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D009765:Obesity / Q000503:physiopathology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D014661:Vasoconstriction / Q000502:physiology
chemical_list: D017382:Reactive Oxygen Species; D018124:Receptors, Tumor Necrosis Factor