Cerebral Vascular Dysfunction During Hypercholesterolemia

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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 −/− mice on the high-fat diet (16±2%, P −/− 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.

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