Decreased EDHF‐mediated relaxation is a major mechanism in endothelial dysfunction in resistance arteries in aged mice on prolonged high‐fat sucrose diet

High‐fat sucrose (HFS) diet in aged individuals causes severe weight gain (obesity) with much higher risk of cardiovascular diseases such as hypertension or atherosclerosis. Endothelial dysfunction is a major contributor for these vascular disorders. We hypothesize that prolonged ingestion of HFS diet by aged mice would accentuate endothelial dysfunction in the small resistance arteries. Male C57BL/6J mice at 12 weeks of age were divided into four groups and fed either normal chow (NC) or high‐fat sucrose diet (HFS). Young group received NC for 4 months, and high‐fat diet (HFD) for 3 months and 1 month HFS + 10% Sucrose (HFS diet). Aged mice received NC for 12 months. Aged HFS group received HFD for 4 months + 1 month HFD + 10% sucrose + 8 months HFD. Total body weight, plasma blood glucose levels, and glucose tolerance were determined in all groups. Isolated mesenteric arteries were assessed for arterial remodeling, myogenic tone, and vasomotor responses using pressure and wire myography. Both young and aged HFS mice showed impaired glucose tolerance (Y‐NC, 137 ± 8.5 vs. Y‐NC HFS, 228 ± 11.71; A‐NC, 148 ± 6.42 vs. A‐HFS, 225 ± 10.99), as well as hypercholesterolemia (Y‐NC 99.50 ± 6.35 vs. Y‐HFS 220.40 ± 16.34 mg/dL; A‐NC 108.6 ± vs. A‐HFS 279 ± 21.64) and significant weight gain (Y‐NC 32.13 ± 0.8 g vs. Y‐HFS 47.87 ± 2.18 g; A‐NC 33.72 vs. A‐HFS 56.28 ± 3.47 g) compared to both groups of mice on NC. The mesenteric artery from mice with prolonged HFS diet resulted in outward hypertrophic remodeling, increased stiffness, reduced myogenic tone, impaired vasodilation, increased contractility and blunted nitric oxide (NO) and EDH‐mediated relaxations. Ebselen, a peroxinitrite scavenger rescued the endothelium derived relaxing factor (EDHF)‐mediated relaxations. Our findings suggest that prolonged diet‐induced obesity of aged mice can worsen small resistance artery endothelial dysfunction due to decrease in NO and EDHF‐mediated relaxation, but, EDHF‐mediated relaxation is a major contributor to overall endothelial dysfunction.