Rodríguez José A, Nespereira Beatriz, Pérez-Ilzarbe Maitane, Eguinoa Ezequiel, Páramo José A
Atherosclerosis Research Laboratory, Division of Cardiovascular Pathophysiology, School of Medicine, Foundation for Applied Medical Research, University of Navarra, Pamplona Navarra E-31008, Spain.
Cardiovasc Res. 2005 Feb 15;65(3):665-73. doi: 10.1016/j.cardiores.2004.08.006.
Vascular endothelial growth factor (VEGF) is believed to play a role in the development of atherosclerosis and has been found to be increased in hypercholesterolemia. We examined the hypothesis that endothelial VEGF and VEGF receptor-2 (VEGFR-2) expression is upregulated by hypercholesterolemic low-density lipoprotein (LDL) and, because it could be driven by oxidative stress, we tested whether vitamin C and E supplementation could modulate it.
Native LDL were characterized after isolation from adult normal (C-LDL), hypercholesterolemic (HC-LDL) and hypercholesterolemic mini-pigs receiving vitamins C and E (HCV-LDL). VEGF, VEGFR-2, HIF-1 alpha and superoxide anion (O(2)(-)) productions were measured in porcine coronary endothelial cells (ECs) incubated for 48 h with native LDL. The effect of exogenous ascorbic acid and alpha- or beta-tocopherol was also studied.
HC-LDL, with high cholesterol (P<0.05) and reduced tocopherol/cholesterol ratio (P<0.05), increased significantly VEGF and VEGFR-2 (p<0.001) in EC, associated with higher O(2)(-) and HIF-1 alpha expression, in comparison with C-LDL and HCV-LDL. The addition of vitamin C and alpha- or beta-tocopherol to the culture medium prevented the induction of VEGF and VEGFR-2 expression by HC-LDL, both at mRNA and protein levels.
Our data suggest HC-LDL induce endothelial VEGF and VEGFR-2 overexpression at least by increasing oxidative stress, and HIF-1 alpha is one of the signaling mechanisms involved. Prevention of VEGF and VEGFR-2 upregulation could help explain the beneficial effects of vitamins C and E in hypercholesterolemia-induced experimental atherosclerosis.
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，并且已发现在高胆固醇血症中其水平会升高。我们检验了以下假设：高胆固醇血症的低密度脂蛋白（LDL）会上调内皮VEGF和VEGF受体-2（VEGFR-2）的表达，并且由于其可能由氧化应激驱动，我们测试了补充维生素C和E是否可以调节这种表达。
从成年正常（C-LDL）、高胆固醇血症（HC-LDL）以及接受维生素C和E的高胆固醇血症小型猪（HCV-LDL）中分离出天然LDL并进行特性分析。在与天然LDL孵育48小时的猪冠状动脉内皮细胞（ECs）中测量VEGF、VEGFR-2、缺氧诱导因子-1α（HIF-1α）和超氧阴离子（O₂⁻）的产生。还研究了外源性抗坏血酸和α-或β-生育酚的作用。
与C-LDL和HCV-LDL相比，HC-LDL胆固醇含量高（P<0.05）且生育酚/胆固醇比值降低（P<0.05），可显著增加EC中VEGF和VEGFR-2的表达（p<0.001），同时伴有更高的O₂⁻和HIF-1α表达。在培养基中添加维生素C和α-或β-生育酚可在mRNA和蛋白质水平上阻止HC-LDL诱导VEGF和VEGFR-2的表达。
我们的数据表明，HC-LDL至少通过增加氧化应激诱导内皮VEGF和VEGFR-2的过表达，并且HIF-1α是其中涉及的信号传导机制之一。预防VEGF和VEGFR-2的上调可能有助于解释维生素C和E在高胆固醇血症诱导的实验性动脉粥样硬化中的有益作用。
