title: 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 microm] 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 Nomega-nitro-L-arginine (L-NNA) reduced baseline diameter from 17.9 +/- 1.2 to 15.9 +/- 1.3 microm (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)]. t50 was 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 t50 only in "slow" responders (t50 > or = 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.
authors.affiliation: Dept. of Medical Physics, Academic Medical Center, PO Box 22700, 1100 DE Amsterdam, The Netherlands. j.w.vanteeffelen@amc.uva.nl
authors.forename: Jurgen W G E
authors.initials: JW
authors.lastname: VanTeeffelen
authors.forename: Alina A
authors.initials: AA
authors.lastname: Constantinescu
authors.forename: Hans
authors.initials: H
authors.lastname: Vink
authors.forename: Jos A E
authors.initials: JA
authors.lastname: Spaan
mesh_terms: D000005:Abdomen; D000818:Animals; D053318:Apolipoprotein E3; D001057:Apolipoproteins E / Q000235:genetics; D001160:Arterioles / Q000187:drug effects / Q000503:physiopathology; D006937:Hypercholesterolemia / Q000150:complications / Q000503:physiopathology*; D006940:Hyperemia / Q000150:complications / Q000503:physiopathology*; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000235:genetics; D018482:Muscle, Skeletal / Q000098:blood supply*; D009599:Nitroprusside / Q000494:pharmacology; D013314:Stress, Mechanical; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D053318:Apolipoprotein E3; D001057:Apolipoproteins E; D008055:Lipids; D014665:Vasodilator Agents; C052720:apolipoprotein E3 (Leidein); D009599:Nitroprusside