Influence of hypercholesterolemia and hypertension on the integrity of the blood-brain barrier in rats.

摘要

Hypercholesterolemia and/or hypertension impair endothelial function in peripheral vasculature; however, their impact on endothelial cells of brain microvessels is unclear. We investigated the effects of hypercholesterolemia on the integrity of the blood-brain barrier (BBB) and the activity of astrocytes during N(omega)-nitro-L-arginine methyl ester (L-NAME) hypertension followed by angiotensin (ANG) II. We found significant decreases in superoxide dismutase levels with all treatments except ANG II and L-NAME plus ANG II, and in catalase concentrations except ANG II and cholesterol plus L-NAME. Nitric oxide (NO) concentrations were significantly decreased by L-NAME but significantly increased by cholesterol. L-NAME-stimulated plasma malondialdehyde (MDA), Ox-LDL, and cholesterol levels were significantly augmented by cholesterol. Glutathione (GSH) levels significantly decreased, while MDA, TNF-alpha, and Ox-LDL levels significantly increased in cholesterol and/or L-NAME. The increase in BBB permeability by acute hypertension in hypercholesterolemic hypertensive animals was less than that observed in chronically hypertensive animals. Brain vessels of L-NAME-treated animals showed a considerable loss of immunoreactivity for tight junction proteins, occludin, and ZO-1. Immunoreactivity for occludin and ZO-1 increased in cholesterol plus L-NAME and decreased in cholesterol. Glial fibrillary acidic protein (GFAP) immunoreactivity was seen in few astrocytes in the brain sections of L-NAME-treated animals, but increased in cholesterol plus L-NAME. Positive immunoreactivity for vascular endothelial growth factor (VEGF) was observed in cholesterol and cholesterol plus L-NAME plus ANG II. We suggest that hypercholesterolemia may affect BBB integrity through increasing the expression of tight junction proteins and GFAP and leading to the production of VEGF, at least partly, via increased NO, TNF-alpha, and catalase in hypertensive conditions.