Affiliation:
1. From the Cardiovascular Center and Departments of Internal Medicine and Pharmacology, University of Iowa Roy J. and Lucille A. Carver College of Medicine and VA Medical Center, Iowa City, Iowa.
Abstract
Background and Purpose—
Studies of peripheral arteries in hypercholesterolemic animals suggest that increased generation of superoxide contributes to endothelial dysfunction, especially in the presence of atherosclerotic lesions. We tested the hypothesis that vasomotor function is impaired in cerebral arterioles during hypercholesterolemia through a mechanism that involves oxidative stress.
Methods—
Apolipoprotein E–deficient (apoE
−/−
) mice were fed a normal or a high-fat diet for >6 months. ApoE
+/−
mice fed a normal diet were used as normocholesterolemic controls. Responses of cerebral arterioles were examined in open cranial windows in vivo in anesthetized mice.
Results—
In apoE
−/−
mice, intimal area was increased only in the proximal aorta on the normal diet and also markedly increased in the distal aorta on the high-fat diet. There were no increases in intimal area in the aortas of control mice or in the cerebral arterioles in any group. The dilator response of cerebral arterioles to ACh (10 μmol/L) in control mice (26±4% increase in diameter) was reduced in apoE
−/−
mice on either the normal (13±2%) or the high-fat (13±3%) diet (
P
<0.05 vs control). NADPH (10 μmol/L), a substrate for NADPH oxidase, produced dilator responses in control mice (8±4%) that were significantly increased in apoE
−/−
mice on the high-fat diet (16±2%,
P
<0.05 vs control). Tempol, a superoxide scavenger, and apocynin, an inhibitor of NADPH oxidase, significantly increased vasodilator responses to ACh and decreased vasodilation to NADPH in apoE
−/−
mice on the high-fat diet. Nitroprusside produced a similar dilatation in the cerebral arterioles of all groups.
Conclusions—
Hypercholesterolemia is associated with oxidative stress and endothelial dysfunction in cerebral arterioles, despite the absence of atherosclerotic lesions.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Advanced and Specialized Nursing,Cardiology and Cardiovascular Medicine,Neurology (clinical)
Cited by
75 articles.
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