Rescue of hypercholesterolemia-related impairment of angiogenesis by oral folate supplementation.

OBJECTIVES We examined whether oral folate supplementation would rescue a hypercholesterolemia (HC)-related impairment of ischemia-induced angiogenesis. BACKGROUND Folate protects against endothelial dysfunction, but the effect of folate supplementation on angiogenesis is little known. METHODS Sprague-Dawley rats were divided into four groups. Control rats were fed a normal diet (n = 18); HC rats (n = 18) were fed 2% cholesterol diet; and HC + folate (HC+F) rats were fed an HC diet with oral folate (0.003% in water). The left femoral artery and vein were surgically excised, and angiogenesis in the ischemic limb was evaluated. We also examined the effects of Nomega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthase, on angiogenesis in the HC+F state. RESULTS Laser Doppler blood flow (LDBF) analysis showed lower ischemic/normal LDBF ratio in the HC group than in the control group. Angiographic and histologic analyses on day 14 revealed a smaller angiographic score (p < 0.001) and capillary density (p < 0.001) in the HC group than in controls, which were associated with reduced tissue NOx and cyclic guanosine monophosphate (cGMP) levels. The LDBF ratio, angiographic score, and capillary density were significantly restored in the HC+F group (p < 0.01 vs. HC), which were associated with increased serum folate and tissue NOx and cGMP levels. Finally, L-NAME treatment abolished the beneficial action of folate on angiogenesis in the HC state. CONCLUSIONS Ischemia-induced angiogenesis was inhibited by HC, which was rescued by oral folate supplementation, at least in part, via an NO-dependent manner.