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 α- or β-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 α-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 β-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.