Endothelial Cell CD36 ablation attenuates obesity-induced endothelial dysfunction in obesity

Obesity is a complex metabolic disease that is the leading risk factor for cardiovascular disease. In obesity, adipose arteries exhibit robust endothelial dysfunction (ED). A major hallmark of ED is loss in flow induced vasodilation (FIV). Kir2.1 is an inwardly rectifying K+ channel that contributes to FIV through the downstream production of nitric oxide, a potent vasodilator. Work from our group demonstrated that in addition to loss in FIV, endothelial cells (ECs) isolated from obese mice exhibited blunted Kir2.1 currents. Plasma long chain fatty acids (LCFAs) are well established to be elevated in obesity and have been separately shown to inhibit Kir2.1 channels. CD36 is the major fatty acid translocase responsible for the uptake of LCFAs and we therefore aimed to determine if CD36 was contributing to this loss in Kir2.1 function. We previously showed that global CD36 ablation restores endothelium-dependent dilations to flow. These findings prompted us to explore the role of EC CD36 in negatively regulating Kir2.1 function. We performed patch clamp electrophysiology experiments on freshly isolated ECs from the Tie2eCreCD36fl/fl model and determined that EC CD36 ablation restores Kir2.1 currents in obesity. To further explore the established relationship between Kir2.1 and FIV, we performed ex vivo pressure myography experiments to evaluate endothelial dependent dilations to flow. EC CD36 ablation restored responses to flow in arteries from obese mice, an effect that could be blunted by inhibiting Kir2.1 suggesting that CD36 ablation in endothelium rescues the Kir2.1 contribution to FIV. To determine if obesity alters the expression of endothelial CD36, arteries from mice and humans undergoing bariatric surgery were isolated and en face preparations were stained to locate the EC layer and assess CD36 expression. Confocal imaging of en face arteries coupled with flow cytometry on isolated endothelial cells revealed that obesity did not alter the expression of CD36 in endothelium of mesenteric arteries relative to controls in WT mice or humans. As expression did not change, we next probed functionality of CD36 in obese vs. control in mice and humans. Arteries were exposed to a fluorescent fatty acid, BODIPY C-16, at various time points followed by en face preparations and confocal microscopy. As expected, obese vessels exhibited elevated amounts of fatty acid uptake (FAU) at all time points relative to control in mice and humans, suggesting an increase in CD36. To further confirm this change in function, we repeated FAU experiments in the Tie2eCreCD36fl/fl model and found that EC CD36 ablation attenuated FAU in obese vessels compared to both their lean and genotype controls. Taken together, this work suggests that an increase in CD36 function drives impairment of Kir2.1. This work establishes a CD36/Kir2.1 axis worthy of further exploration including understanding how CD36 and LCFAs are impairing Kir2.1 upstream. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.