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

Abstract

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.

Rethinking Endothelial Dysfunction as a Crucial Target in Fighting Heart Failure

“…Nitric oxide is the predominant mediator of vasodilatation, but other endogenous factors such as bradykinin, acetylcholine (Ach), catecholamines, endothelium-derived hyperpolarizing factor (EDHF), and prostacyclin also play a role. In fact, emerging research suggests that diminished EDHF-mediated vasodilation is a major contributor to endothelial dysfunction, since EDHF is crucial for small resistance artery relaxation, especially in the setting of high cholesterol or diabetes 6, 7, 8. Furthermore, the endothelium produces antiproliferative and anti-inflammatory cytokines as well as regulates the coagulation cascade through a balanced production of anticoagulant and procoagulant factors.…”

Surgical castration versus chemical castration in donkeys: response of stress, lipid profile and redox potential biomarkers

“…Monitoring the temporal changes in plasma lipoproteins following castration may provide a better understanding their metabolic regulation under conditions of androgen deprivation. Disturbance in lipid metabolism evokes adverse consequences such as insulin resistance, hypertension, inflammation, and endothelial dysfunction [11][12][13][14].…”

Short‐term very low caloric intake causes endothelial dysfunction and increased susceptibility to cardiac arrhythmias and pathology in male rats

“…Endothelial dysfunction occurs in hypertension and other cardiovascular diseases (Rodrigo et al, 1997;Strawn, Gallagher, Dean, Ganten, & Ferrario, 1997). There are also many examples of endothelial dysfunction in animal models of diet-induced obesity and diabetes (Bhatta et al, 2017;Dunn, Hilgers, & Das, 2017;Zuloaga et al, 2016). There is much less known regarding endothelial dysfunction during caloric restriction.…”