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1 Department of Medical Physics, Cardiovascular Research Institute Amsterdam, Academic Medical Center, Amsterdam, The Netherlands
* To whom correspondence should be addressed. E-mail: j.w.vanteeffelen{at}amc.uva.nl.
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 (2A & 3A; 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 control and high fat/high cholesterol (HFC) fed C57Bl/6 and ApoE3-Leiden 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 NO synthesis with N
-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 (t50 of recovery: 23.3 ± 3.6 s vs. 12.5 ± 1.3 s (P=0.003). t50 was longer in 2A vs. 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 to 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 
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 reactive hyperemia. 2A arterioles likely therefore represent the functional locus of endothelial dysfunction during atherogenic conditions.
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