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Mechanisms of Microvascular Endothelial Dysfunction in Subcutaneous Fat during Human Obesity

Microvascular endothelial dysfunction contributes to cardiovascular disease risk during obesity. Inflammatory cytokines (CRP and IL‐6) and NADPH oxidase generation of reactive oxygen species (ROS) reduces endothelial function during obesity. Therefore, we hypothesized that pro‐ inflammatory cytokines and NADPH oxidase generation of ROS contribute to microvascular dysfunction in subcutaneous (SQ) fat during obesity. Isolated resistance arteries were obtained from SQ biopsies in lean (LN; BMI<27) and during laproscopic band surgery in obese (OB; BMI>40) women (mean age: 36±1). Microvessels were cannulated for vascular reactivity measurements to acetylcholine (ACh; 10−9‐10−4 M) in the absence and presence of the SOD mimetic Tiron (10−4 M), NADPH oxidase inhibitor apocynin (10−6 M), and the xanthine oxidase inhibitor allopurinol (10−4 M). Superoxide production was assessed with hydroethidine fluorescence in the presence and absence of the same inhibitors. Blood measurements of CRP and IL‐6 were determined with ELISA. Maximum dilation to ACh was reduced in OB (46 ± 6%; n=9; p<0.05) vs. LN (79 ± 9%; n=5) patients and was restored by Tiron. Superoxide production was increased in microvessels from OB subjects. Tiron and apocynin restored the dilator response to ACh and reduced baseline and ACh‐ stimulated superoxide fluorescence of OB. Allopurinol had no effect on ACh responses in OB microvessels. There was no association between IL‐6 or CRP and superoxide fluorescence. These data indicate that NADPH oxidase generation of ROS impairs endothelial function in SQ microvessels during obesity.