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Vascular Generation of Tumor Necrosis Factor-α Reduces Nitric Oxide Availability in Small Arteries From Visceral Fat of Obese Patients
Study Questions:
What is the role of vascular tumor necrosis factor-alpha (TNF-α) on reactive oxygen species (ROS) generation and nitric oxide (NO) availability?
Methods:
Small arteries from 14 obese (body mass index 48.4 ± 11 kg/m2) and 14 control subjects (body mass index 24.9 ± 2 kg/m2), dissected after a visceral fat biopsy (laparoscopy), were evaluated on a pressurized micromyograph. Endothelium-dependent relaxation was assessed by acetylcholine. The NO availability, superoxide production, and inflammation were assessed by testing acetylcholine under the nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine methylester, tempol (superoxide scavenger), and infliximab (monoclonal anti–TNF-α antibody), respectively. The roles of nicotinamide adenine dinucleotide phosphate oxidase and inducible nitric oxide synthase (iNOS) were assessed by their selective inhibitors apocynin and S-methylisothiourea (SMT), respectively. Vascular superoxide generation (dihydroethidium staining) protein expression of TNF-α and NOS isoforms (Western Blot) and TNF-α localization (immunohistochemistry) were assessed.
Results:
Vessels from obese patients displayed a blunted relaxation to acetylcholine and a reduced inhibitory effect of Nω-nitro-L-arginine methylester. These alterations were normalized by tempol or infliximab while being partly ameliorated by apocynin and SMT. Vascular superoxide generation was increased (p < 0.01) in obese patients. This condition was abrogated by both tempol and infliximab, and partly (p < 0.05 vs. control subjects) reduced by apocynin or SMT. Enhanced TNF-α and iNOS expression, together with increased TNF-α localization in the vascular media, were detected.
Conclusions:
The authors concluded that small arteries from visceral fat of obese patients are characterized by an increased TNF-α production, which reduces NO availability by promoting superoxide generation via nicotinamide adenine dinucleotide phosphate oxidase and iNOS activation.
Perspective:
This study suggests that small resistance arteries, isolated from the visceral adipose tissue of patients with severe obesity, are characterized by a marked endothelial dysfunction caused by a reduced NO availability. This alteration results from an increased vascular production and biological activity of TNF-α, which promotes superoxide generation via both NAD(P)H oxidase and iNOS activation. These findings, while supporting the concept that obesity is an inflammatory condition, identify the small vessels of visceral fat as important sources of low-grade inflammation and oxidative stress that, together with the perivascular adipose tissue, may directly contribute to the local development of insulin resistance seen in obese patients.
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