title: Vitamins C and E downregulate vascular VEGF and VEGFR-2 expression in apolipoprotein-E-deficient mice.
abstract: 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 beta-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 alpha-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 beta-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.
authors.affiliation: Atherosclerosis Research Unit, University of Navarra, C/Irunlarrea 1. CIFA, Pamplona E-31008, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Nespereira
authors.forename: Maitane
authors.initials: M
authors.lastname: Pérez-Ilzarbe
authors.forename: Patricia
authors.initials: P
authors.lastname: Fernández
authors.forename: Angela M
authors.initials: AM
authors.lastname: Fuentes
authors.forename: José A
authors.initials: JA
authors.lastname: Páramo
authors.forename: José A
authors.initials: JA
authors.lastname: Rodríguez
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000187:drug effects*; D001205:Ascorbic Acid / Q000097:blood / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D002784:Cholesterol / Q000097:blood; D019587:Dietary Supplements; D015536:Down-Regulation / Q000187:drug effects*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D008955:Models, Cardiovascular; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000008:administration & dosage; D014280:Triglycerides / Q000097:blood; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000097:blood / Q000187:drug effects*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis* / Q000097:blood / Q000187:drug effects*; D014810:Vitamin E / Q000097:blood / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D001057:Apolipoproteins E; D015415:Biomarkers; D012333:RNA, Messenger; D017392:Thiobarbituric Acid Reactive Substances; D014280:Triglycerides; D042461:Vascular Endothelial Growth Factor A; D014810:Vitamin E; D002784:Cholesterol; D040301:Vascular Endothelial Growth Factor Receptor-2; D001205:Ascorbic Acid