title: Local inflammation and hypoxia abolish the protective anticontractile properties of perivascular fat in obese patients.
abstract: BACKGROUND
  Inflammation in adipose tissue has been implicated in vascular dysfunction, but the local mechanisms by which this occurs are unknown.
  
  
  RESULTS
  Small arteries with and without perivascular adipose tissue were taken from subcutaneous gluteal fat biopsy samples and studied with wire myography and immunohistochemistry. We established that healthy adipose tissue around human small arteries secretes factors that influence vasodilation by increasing nitric oxide bioavailability. However, in perivascular fat from obese subjects with metabolic syndrome (waist circumference 111+/-2.8 versus 91.1+/-3.5 cm in control subjects, P<0.001; insulin sensitivity 41+/-5.9% versus 121+/-18.6% in control subjects, P<0.001), the loss of this dilator effect was accompanied by an increase in adipocyte area (1786+/-346 versus 673+/-60 mum(2), P<0.01) and immunohistochemical evidence of inflammation (tumor necrosis factor receptor 1 12.4+/-1.1% versus 6.7+/-1%, P<0.001). Application of the cytokines tumor necrosis factor receptor-alpha and interleukin-6 to perivascular fat around healthy blood vessels reduced dilator activity, resulting in the obese phenotype. These effects could be reversed with free radical scavengers or cytokine antagonists. Similarly, induction of hypoxia stimulated inflammation and resulted in loss of anticontractile capacity, which could be rescued by catalase and superoxide dismutase or cytokine antagonists. Incubation with a soluble fragment of adiponectin type 1 receptor or inhibition of nitric oxide synthase blocked the vasodilator effect of healthy perivascular adipose tissue.
  
  
  CONCLUSIONS
  We conclude that adipocytes secrete adiponectin and provide the first functional evidence that it is a physiological modulator of local vascular tone by increasing nitric oxide bioavailability. This capacity is lost in obesity by the development of adipocyte hypertrophy, leading to hypoxia, inflammation, and oxidative stress.
authors.affiliation: Cardiovascular Research Group, University of Manchester, Manchester, United Kingdom.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Greenstein
authors.forename: Kaivan
authors.initials: K
authors.lastname: Khavandi
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Withers
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Sonoyama
authors.forename: Olivia
authors.initials: O
authors.lastname: Clancy
authors.forename: Maria
authors.initials: M
authors.lastname: Jeziorska
authors.forename: Ian
authors.initials: I
authors.lastname: Laing
authors.forename: Allen P
authors.initials: AP
authors.lastname: Yates
authors.forename: Philip W
authors.initials: PW
authors.lastname: Pemberton
authors.forename: Rayaz A
authors.initials: RA
authors.lastname: Malik
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Heagerty
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism; D000273:Adipose Tissue; D000818:Animals; D001808:Blood Vessels / Q000503:physiopathology*; D016022:Case-Control Studies; D016207:Cytokines / Q000494:pharmacology; D006801:Humans; D006984:Hypertrophy; D000860:Hypoxia / Q000503:physiopathology*; D007249:Inflammation / Q000503:physiopathology*; D007333:Insulin Resistance; D008297:Male; D024821:Metabolic Syndrome / Q000473:pathology; D008875:Middle Aged; D009569:Nitric Oxide / Q000096:biosynthesis; D009765:Obesity / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation; D055105:Waist Circumference
chemical_list: D052242:Adiponectin; D016207:Cytokines; D009569:Nitric Oxide