Nespereira Beatriz, Pérez-Ilzarbe Maitane, Fernández Patricia, Fuentes Angela M, Páramo José A, Rodríguez José A
Atherosclerosis Research Unit, University of Navarra, C/Irunlarrea 1. CIFA, Pamplona E-31008, Spain.
Atherosclerosis. 2003 Nov;171(1):67-73. doi: 10.1016/j.atherosclerosis.2003.08.009.
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.
抗血管生成疗法可减少载脂蛋白E缺乏小鼠（apoE-/-）的斑块生长和内膜新生血管形成。血管内皮生长因子（VEGF）被认为在动脉粥样硬化的发展中起作用。我们检验了这样一个假设，即apoE-/-中VEGF和VEGF受体-2（VEGFR-2）的表达上调，并且由于其可能由氧化应激驱动，因此测试了维生素C和E的膳食补充是否可以下调其表达。两个月大的apoE-/-小鼠接受维生素C与α-或β-生育酚联合治疗4周。通过RT-qPCR和蛋白质印迹法测量主动脉VEGF和VEGFR-2的表达。与野生型小鼠相比，apoE-/-小鼠主动脉VEGF和VEGFR-2 mRNA（P<0.001）和蛋白质（P<0.001）的表达显著更高，同时血浆VEGF也增加（P<0.001）。维生素C和α-生育酚显著降低了apoE-/-小鼠主动脉VEGF和VEGFR-2的表达（P<0.001）、循环VEGF（P<0.01）和血浆脂质过氧化（P<0.01）。接受维生素C和β-生育酚的apoE-/-小鼠脂质过氧化和VEGFR-2减少，但VEGF表达仅部分降低。这些数据表明，apoE-/-血管系统中VEGF和VEGFR-2表达的增加可被维生素C和E下调，至少部分是通过降低氧化应激实现的。这种新机制可能有助于解释抗氧化维生素在实验性动脉粥样硬化中的有益作用。
