Hypercholesterolemia impairs reactive hyperemic vasodilation of 2A but not 3A arterioles in mouse cremaster muscle

Abstract

Hypercholesterolemia and atherosclerosis have been associated with changes in the microvasculature, in particular with endothelial dysfunction. In the present study, the impact of atherogenic conditions on arteriolar vasomotor control was determined. Arteriolar [second-order (2A) and third-order (3A) arterioles; diameter range: 9–37 μm] responses during reactive hyperemia (RH) were determined in cremaster muscle of anesthetized mice. C57Bl/6 mice on normal rodent chow were used as controls and high-fat/high-cholesterol (HFC)-fed C57Bl/6 and ApoE3-Leiden mice as hypercholesterolemic mice. The HFC diet resulted in time-dependent increases in plasma cholesterol and triglyceride concentrations ( P < 0.001), which were more pronounced in ApoE3-Leiden mice ( P < 0.001). In control mice, inhibition of nitric oxide (NO) synthesis with N^ω-nitro-l-arginine (l-NNA) reduced baseline diameter from 17.9 ± 1.2 to 15.9 ± 1.3 μm ( P < 0.05) and decreased the duration of RH [time to 50% ( t₅₀) of recovery: 23.3 ± 3.6 vs. 12.5 ± 1.3 s ( P = 0.003)]. t₅₀was longer in 2A versus 3A arterioles (33 ± 3 vs. 18 ± 2 s, P < 0.001) and increased with wall shear rate at the beginning of RH in 2A arterioles only. Compared with control mice, RH duration was reduced in 2A arterioles of HFC mice ( t₅₀: 11 ± 2 s, P < 0.001 vs. control) but not affected in 3A vessels. l-NNA did not affect baseline diameter in HFC mice and reduced t₅₀only in “slow” responders ( t₅₀≥ 10 s). It is concluded that hypercholesterolemia results in an impairment of NO-mediated vasomotor control in 2A but not 3A arterioles during dynamic changes of perfusion like RH. 2A arterioles likely therefore represent the functional locus of endothelial dysfunction during atherogenic conditions.