Endothelial dysfunction can be reversed in obese humans and mice by overexpression of endothelial Kir2.1 channels

Abstract

The vascular endothelium is an important regulator of vascular tone. Acute changes in mechanical stressors, such as blood flow (fluid shear) and pressure, are converted into chemical signals by the endothelium to control vasomotor function. We recently showed that endothelial Kir2.1 channels are critical to the vasodilatory response to increases in blood flow through eNOS and NO production. It is well established that obesity causes endothelial dysfunction likely through impairment of nitric oxide signaling/bioavailability. Furthermore, obesity impairs the vasculature of visceral adipose depots while arteries in the subcutaneous adipose appear unaffected. Therefore, we tested the role of endothelial Kir2.1 in obesity‐induced endothelial dysfunction in vascular beds of spatially distinct adipose depots in obese humans and in a diet‐induced obese mouse model. Mice were fed a high fat, high cholesterol diet for 4 or 8 weeks prior to analysis of vascular function via response to flow in an ex vivo arterial preparation. Endothelial function of arteries from both subcutaneous and visceral adipose depots were tested. After 4 weeks of high fat feeding, no differences were observed in vascular function between arteries from either adipose depot nor when compared to control mice fed a normal chow diet. However, after 8 weeks visceral arteries from high fat fed mice had a significantly blunted response to flow, while subcutaneous arteries retained a full dilatory response. Overexpressing endothelial Kir2.1 using adenoviral transduction with expression driven by the VE‐Cadherin promoter in visceral arteries of diet‐induced obese mice rescued the response to flow suggesting that Kir2.1 channel function or expression may be impaired exclusively in arteries of visceral adipose of obese mice. Importantly, we observed similar findings in obese human arteries from visceral and subcutaneous adipose biopsies collected during bariatric surgery.Support or Funding InformationNIH R01 HL073965 (IL)American Heart Association 16POST27000011 (ISF)NIH 5T32HL007829‐24 (ISF)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.