Effects of dietary folic acid supplementation on cerebrovascular endothelial dysfunction in rats with induced hyperhomocysteinemia

This study shows, for the first time, that hyperhomocysteinemia induces endothelial dysfunction in a rat brain, and that this can be alleviated by dietary folic acid supplementation. Our experiments examined the effects of folic acid supplementation on the endothelial nitric oxide synthase (eNOS) expression in the hyperhomocysteinemic rat brain, and related the observed changes in eNOS expression to the expression of the cell adhesion molecule and the glucose transporter protein. The animals were raised on an experimental diet containing 0.3% homocystine for 2 weeks and then they were placed either on a 0.3% homocystine, 0.3% homocystine with 8 mg/kg folic acid, or folic acid (8 mg/kg) diet for 2 weeks. The cerebrovascular eNOS activity was examined immunohistochemically. Cerebral levels of eNOS, glucose transporter-1 (GLUT-1), and the vascular cell adhesion molecule-1 (VCAM-1) proteins were evaluated by Western blot analysis. At 4 weeks, the homocystine diet induced a fourfold increase in plasma homocysteine (control: 6.5±0.4 μmol/l, homocystine: 26.2±2.5 μmol/l), and a reduction in the cerebral eNOS and GLUT-1 expression levels with a concomitant increase in the level of VCAM-1 expression. Dietary folic acid supplementation caused a significant decrease in the plasma homocysteine levels, a concomitant increase in the hyperhomocysteinemia-induced reduction in the cerebral eNOS and GLUT-1 expression levels, and a decrease in the hyperhomocysteinemia-induced VCAM-1 expression levels.