Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury
Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury
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DOI：
10.2353/ajpath.2007.061237
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发表时间：
2007-07-01
影响因子：
6
通讯作者：
Shima, David T.
中科院分区：
文献类型：
--
作者：
Nishijima, Kazuaki;Ng, Yin-Shan;Shima, David T.
血管内皮生长因子- a （VEGF-A）近年来被认为是中枢神经系统中重要的神经保护剂。鉴于其在人类疾病治疗中的抗血管生成靶点地位，了解VEGF在神经细胞存活中的作用程度是至关重要的。在这里，我们使用了一个缺血再灌注损伤模型，发现VEGF-A暴露导致视网膜神经元凋亡的剂量依赖性减少。虽然机制研究表明VEGF-A诱导的容量血如何进入视网膜可能是神经保护的部分原因，但离体视网膜培养表明VEGF-A具有直接的神经保护作用。VEGF受体-2 （VEGFR2）在视网膜的多个神经元细胞层中表达，功能分析表明VEGFR2参与视网膜神经保护。VEGF-A也被证明参与视网膜缺血的适应性反应。缺血再灌注损伤前24小时缺血预处理可增加VEGF-A水平，并显著减少视网膜细胞凋亡数量。VEGF-A抑制后，缺血预处理的保护作用被逆转。最后，在正常成年动物中，慢性抑制VEGF-A功能导致视网膜神经节细胞的显著损失，但对几种血管参数没有明显影响。这些发现对神经病变和眼部血管疾病，如糖尿病视网膜病变和年龄相关性黄斑变性都有意义。
Vascular endothelial growth factor-A (VEGF-A) has recently been recognized as an important neuroprotectant in the central nervous system. Given its position as an anti-angiogenic target in the treatment of human diseases, understanding the extent of VEGF's role in neural cell survival is paramount. Here, we used a model of ischemia-reperfusion injury and found that VEGF-A exposure resulted in a dose-dependent reduction in retinal neuron apoptosis. Although mechanistic studies suggested that VEGF-A-induced volumetric blood How to the retina may be partially responsible for the neuroprotection, ex vivo retinal culture demonstrated a direct neuroprotective effect for VEGF-A. VEGF receptor-2 (VEGFR2) expression was detected in several neuronal cell layers of the retina, and functional analyses showed that VEGFR2 was involved in retinal neuroprotection. VEGF-A was also shown to be involved in the adaptive response to retinal ischemia. Ischemic preconditioning 24 hours before ischemia-reperfusion injury increased VEGF-A levels and substantially decreased the number of apoptotic retinal cells. The protective effect of ischemic preconditioning was reversed after VEGF-A inhibition. Finally, chronic inhibition of VEGF-A function in normal adult animals led to a significant loss of retinal ganglion cells yet had no observable effect on several vascular parameters. These findings have implications for both neural pathologies and ocular vascular diseases, such as diabetic retinopathy and age-related macular degeneration.