Obesity Differentially Effects Visceral vs. Subcutaneous Adipose Arteries: Role of Shear Activated Kir2.1 and Alterations to the Glycocalyx in Mediating Endothelial Dysfunction

Obesity imposes well-established deficits to endothelial function; however, obesity-induced endothelial dysfunction is not observed in all vascular beds. Visceral adipose arteries (VAA), but not subcutaneous adipose arteries (SAA), exhibit endothelial dysfunction. Here we aimed to determine if differences in SAA vs. VAA endothelial function observed in obesity are attributed to differential impairment of Kir channels and alterations to the glycocalyx. We used a mouse model of diet-induced obesity and recruited obese human subjects undergoing planned bariatric surgery to this study. The effects of obesity on flow-induced vasodilation (FIV) in VAA and SAA were assessed ex vivo. Functional downregulation of endothelial Kir2.1 was accomplished by transducing adipose arteries from mice and obese humans with adenovirus containing a dominant-negative Kir2.1 construct. Kir function was tested in freshly isolated endothelial cells seeded in a flow chamber for electrophysiological recordings under fluid shear. Atomic force microscopy was used to assess biophysical properties of the glycocalyx. Endothelial dysfunction was observed in VAA of obese mice and humans. Downregulating Kir2.1 blunted FIV in SAA, but had no effect on VAA, from obese mice and humans. Kir shear-sensitivity was observed in SAA endothelial cells from obese mice and effects on SAA glycocalyx were mild. In contrast, Kir shear-sensitivity was abolished in VAA endothelial cells and the biophysical properties of the VAA glycocalyx was significantly exacerbated in VAA of obese mice. Our findings show differences in Kir function and alterations to the glycocalyx that we propose contribute to the dichotomy in SAA vs. VAA endothelial function with obesity. © FASEB.