Human vascular endothelial growth factor protects axotomized retinal ganglion cells in vivo by activating ERK-1/2 and Akt pathways
Human vascular endothelial growth factor protects axotomized retinal ganglion cells in vivo by activating ERK-1/2 and Akt pathways
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DOI：
10.1523/jneurosci.0434-06.2006
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发表时间：
2006-11-29
影响因子：
5.3
通讯作者：
Hermann, Dirk M.
中科院分区：
文献类型：
--
作者：
Kilic, Ulkan;Kilic, Ertugrul;Hermann, Dirk M.
基于对神经元和血管细胞的营养作用，血管内皮生长因子(VEGF)有望成为治疗神经退行性疾病的候选药物。为了评估血管内皮生长因子的治疗潜力，我们研究了这种生长因子对轴突视网膜神经节细胞(RGCs)变性的影响，RGCs作为中枢神经系统来源的神经元，在体内为研究神经保护提供了极好的方法。利用在神经元特异性烯醇化酶启动子下组成性表达人血管内皮生长因子的转基因小鼠，我们发现(1)转基因视网膜过度表达人血管内皮生长因子，(2)视网膜节细胞携带血管内皮生长因子受体-2，(3)正常和轴突切除的转基因(TG)视网膜中的血管网络与对照动物没有差别。与野生型小鼠相比，血管内皮生长因子转基因小鼠的视网膜节细胞在切断轴突后可防止延迟性变性。Western blotting显示，转基因视网膜中ERK-1/2和Akt的磷酸化水平增加，p38的磷酸化水平降低，caspase-3的激活水平降低。玻璃体内注射药物ERK-1/2(PD98059)或Akt(LY294002)抑制剂表明，VEGF通过双重激活ERK-1/2和Akt通路发挥神经保护作用。鉴于视神经切断后RGC死亡缓慢，考虑到RGC是中枢神经系统来源的神经元，我们预测血管内皮生长因子在脑和视网膜神经退行性疾病中的临床应用。
Based on its trophic effects on neurons and vascular cells, vascular endothelial growth factor (VEGF) is a promising candidate for the treatment of neurodegenerative diseases. To evaluate the therapeutic potential of VEGF, we here examined effects of this growth factor on the degeneration of axotomized retinal ganglion cells (RGCs), which, as CNS- derived neurons, offer themselves in an excellent way to study neuroprotection in vivo. Making use of a transgenic mouse line that constitutively expresses human VEGF under a neuron-specific enolase promoter, we show that (1) the VEGF-transgenic retina overexpresses human VEGF, (2) RGCs carry the VEGF receptor-2, and (3) vascular networks in normal and axotomized VEGF-transgenic (tg) retinas do not differ from control animals. After axotomy, RGCs of VEGF-tg mice were protected against delayed degeneration, as compared with wild-type littermates. Western blots revealed increased phosphorylated ERK-1/2 and Akt and reduced phosphorylated p38 and activated caspase-3 levels in axotomized VEGF-transgenic retinas. Intravitreous injections of pharmacological ERK-1/2 (PD98059) or Akt (LY294002) inhibitors showed that VEGF exerts neuroprotection by dual activation of ERK-1/2 and Akt pathways. In view that axotomy-induced RGC death occurs slowly and considering that RGCs are CNS-derived neurons, we predict the clinical implementation of VEGF in neurodegenerative diseases of both brain and retina.