Interactions between vascular wall and perivascular adipose tissue reveal novel roles for adiponectin in the regulation of endothelial nitric oxide synthase function in human vessels

Circulation. 2013 Jun 4;127(22):2209-21. doi: 10.1161/CIRCULATIONAHA.112.001133. Epub 2013 Apr 26.


Background: Adiponectin is an adipokine with potentially important roles in human cardiovascular disease states. We studied the role of adiponectin in the cross-talk between adipose tissue and vascular redox state in patients with atherosclerosis.

Methods and results: The study included 677 patients undergoing coronary artery bypass graft surgery. Endothelial function was evaluated by flow-mediated dilation of the brachial artery in vivo and by vasomotor studies in saphenous vein segments ex vivo. Vascular superoxide (O2(-)) and endothelial nitric oxide synthase (eNOS) uncoupling were quantified in saphenous vein and internal mammary artery segments. Local adiponectin gene expression and ex vivo release were quantified in perivascular (saphenous vein and internal mammary artery) subcutaneous and mesothoracic adipose tissue from 248 patients. Circulating adiponectin was independently associated with nitric oxide bioavailability and O2(-) production/eNOS uncoupling in both arteries and veins. These findings were supported by a similar association between functional polymorphisms in the adiponectin gene and vascular redox state. In contrast, local adiponectin gene expression/release in perivascular adipose tissue was positively correlated with O2(-) and eNOS uncoupling in the underlying vessels. In ex vivo experiments with human saphenous veins and internal mammary arteries, adiponectin induced Akt-mediated eNOS phosphorylation and increased tetrahydrobiopterin bioavailability, improving eNOS coupling. In ex vivo experiments with human saphenous veins/internal mammary arteries and adipose tissue, we demonstrated that peroxidation products produced in the vascular wall (ie, 4-hydroxynonenal) upregulate adiponectin gene expression in perivascular adipose tissue via a peroxisome proliferator-activated receptor-γ-dependent mechanism.

Conclusions: We demonstrate for the first time that adiponectin improves the redox state in human vessels by restoring eNOS coupling, and we identify a novel role of vascular oxidative stress in the regulation of adiponectin expression in human perivascular adipose tissue.

Keywords: 5,6,7,8-tetrahydrobiopterin; adiponectin; atherosclerosis; endothelium; nitric oxide synthase type III; superoxides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiponectin / genetics
  • Adiponectin / metabolism*
  • Adipose Tissue / metabolism*
  • Aged
  • Aldehydes / metabolism
  • Coronary Artery Bypass
  • Coronary Artery Disease / metabolism*
  • Coronary Artery Disease / surgery
  • Female
  • Gene Expression / physiology
  • Humans
  • Male
  • Mammary Arteries / metabolism
  • Mammary Arteries / transplantation
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type III / metabolism*
  • Oxidation-Reduction
  • Oxidative Stress / physiology
  • PPAR gamma / metabolism
  • Saphenous Vein / metabolism
  • Saphenous Vein / transplantation
  • Superoxides / metabolism
  • Vasodilation / physiology


  • ADIPOQ protein, human
  • Adiponectin
  • Aldehydes
  • PPAR gamma
  • Superoxides
  • Nitric Oxide
  • NOS3 protein, human
  • Nitric Oxide Synthase Type III
  • 4-hydroxy-2-nonenal