Vascular endothelial growth factor:: Direct neuroprotective effect in in vitro ischemia
Vascular endothelial growth factor:: Direct neuroprotective effect in in vitro ischemia
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DOI：
10.1073/pnas.97.18.10242
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发表时间：
2000-08-29
影响因子：
11.1
通讯作者：
Greenberg, DA
中科院分区：
文献类型：
--
作者：
Jin, KL;Mao, XO;Greenberg, DA
血管内皮生长因子（VEGF）是一种缺氧诱导的血管生成肽，具有神经营养作用。由于一些神经营养因子可以保护神经元免受缺氧或缺血损伤，我们研究了VEGF具有类似神经保护特性的可能性。在HN 33（一种永生化海马神经元细胞系）中，VEGF减少了与脑缺血体外模型相关的细胞死亡：在最大有效浓度为50 ng/ml时，VEGF使缺氧和葡萄糖剥夺24小时后存活的细胞数量大约加倍。为了研究VEGF的神经保护机制，通过Western印迹法测量已知的VEGF靶受体的表达，结果表明HN 33细胞表达VEGFR-2受体和neuropilin-1，而不表达VEGFR-1受体。神经纤毛蛋白-1配体胎盘生长因子-2未能再现VEGF的保护作用，指出VEGFR-2作为VEGF的神经保护作用的位点。两种磷脂酰肌醇3 '-激酶抑制剂wortmannin和LY 294002可逆转VEGF的神经保护作用，表明磷脂酰肌醇3'-激酶/Akt信号转导系统参与了VEGF介导的神经保护作用。VEGF还保护大鼠大脑皮层神经元的原代培养物免受缺氧和葡萄糖剥夺。我们的结论是，除了已知的血管生成因子的作用，VEGF可能发挥直接的神经保护作用，在缺氧缺血性损伤。
Vascular endothelial growth factor (VEGF) is a hypoxia-inducible angiogenic peptide with recently identified neurotrophic effects. Because some neurotrophic factors can protect neurons from hypoxic or ischemic injury, we investigated the possibility that VEGF has similar neuroprotective properties. In HN33, an immortalized hippocampal neuronal cell line, VEGF reduced cell death associated with an in vitro model of cerebral ischemia: at a maximally effective concentration of 50 ng/ml, VEGF approximately doubled the number of cells surviving after 24 h of hypoxia and glucose deprivation, To investigate the mechanism of neuroprotection by VEGF, the expression of known target receptors for VEGF was measured by Western blotting, which showed that HN33 cells expressed VEGFR-2 receptors and neuropilin-1, but not VEGFR-1 receptors. The neuropilin-1 ligand placenta growth factor-2 failed to reproduce the protective effect of VEGF, pointing to VEGFR-2 as the site of VEGF's neuroprotective action. Two phosphatidylinositol 3'-kinase inhibitors, wortmannin and LY294002, reversed the neuroprotective effect of VEGF, implicating the phosphatidylinositol 3'-kinase/Akt signal transduction system in VEGF-mediated neuroprotection. VEGF also protected primary cultures of rat cerebral cortical neurons from hypoxia and glucose deprivation. We conclude that in addition to its known role as an angiogenic factor, VEGF may exert a direct neuroprotective effect in hypoxic-ischemic injury.