Vitamins C and E downregulate vascular VEGF and VEGFR-2 expression in apolipoprotein-E-deficient mice

Anti-angiogenic therapy reduces both plaque growth and intimal neovascularization in apolipoprotein-E-deficient mice (apoE-/-). Vascular endothelial growth factor (VEGF) has been suggested as playing a role in the development of atherosclerosis. We examined the hypothesis that VEGF and VEGF receptor-2 (VEGFR-2) expression is upregulated in apoE-/- and, since it could be driven by oxidative stress, tested whether dietary supplementation with vitamins C and E could downregulate it. Two-month-old apoE-/- received vitamin C combined with alpha- or P-tocopherol for 4 weeks. Aortic VEGF and VEGFR-2 expression were measured by RT-qPCR and western blot. ApoE-/- showed significantly higher expression of aortic VEGF and VEGFR-2 mRNA (P < 0.001) and protein (P < 0.001) than wild-type mice, as well as increased plasma VEGF (P < 0.001). Vitamin C and (x-tocopherol significantly reduced aortic VEGF and VEGFR-2 expression in apoE-/- (P < 0.001), circulating VEGF (P < 0.01) and plasma lipid peroxidation (P < 0.01). apoE-/- receiving vitamin C and P-tocopherol showed diminished lipid peroxidation and VEGFR-2, but only partial reduction of VEGF expression. These data demonstrate that augmented VEGF and VEGFR-2 expression in apoE-/- vasculature can be downregulated by vitamins C and E, at least partially through oxidative stress reduction. This novel mechanism could contribute to explaining the beneficial effects of antioxidant vitamins in experimental atherosclerosis. (C) 2003 Elsevier Ireland Ltd. All rights reserved.