Endogenous VEGF is required for visual function: evidence for a survival role on müller cells and photoreceptors.
Endogenous VEGF is required for visual function: evidence for a survival role on müller cells and photoreceptors.
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DOI：
10.1371/journal.pone.0003554
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发表时间：
2008
期刊：
影响因子：
3.7
通讯作者：
D'Amore PA
中科院分区：
文献类型：
--
作者：
Saint-Geniez M;Maharaj AS;Walshe TE;Tucker BA;Sekiyama E;Kurihara T;Darland DC;Young MJ;D'Amore PA
血管内皮生长因子(VEGF)在正常和病理性新生血管形成中的作用是众所周知的。然而，越来越多的证据表明，无论是在发育中还是在成人中，血管内皮生长因子也作用于非血管细胞。鉴于全身和眼内抗血管内皮生长因子疗法广泛用于治疗与肿瘤生长和湿性黄斑变性相关的血管生成，系统研究血管内皮生长因子在成人视网膜中的作用是至关重要的。利用免疫组织化学和Lac-Z报告鼠系，我们报道了成年小鼠视网膜中各种细胞产生的血管内皮生长因子，以及主要的信号受体VEGFR2的广泛表达，其中Müler细胞和光感受器表达较强。通过sFlt1的腺病毒表达，在小鼠中完成了对血管内皮生长因子的系统中和。血管内皮生长因子中和14d后，内、外视网膜血管无明显变化，内、外核层细胞凋亡率明显增加。四周后，神经细胞死亡的增加与内、外核层厚度的减少以及视网膜电图仪测量的视网膜功能下降有关。基于siRNA的抑制血管内皮生长因子的表达支持血管内皮细胞生长因子在米勒细胞存活中的自分泌作用。同样，在新鲜分离的光感受器细胞和外核层外植体中加入外源血管内皮生长因子，表明血管内皮生长因子具有高度的神经保护作用。这些结果表明内源性血管内皮生长因子在成人视网膜神经细胞的维持和功能中起着重要作用，提示抗血管内皮生长因子治疗应谨慎使用。
Vascular endothelial growth factor (VEGF) is well known for its role in normal and pathologic neovascularization. However, a growing body of evidence indicates that VEGF also acts on non-vascular cells, both developmentally as well as in the adult. In light of the widespread use of systemic and intraocular anti-VEGF therapies for the treatment of angiogenesis associated with tumor growth and wet macular degeneration, systematic investigation of the role of VEGF in the adult retina is critical. Using immunohistochemistry and Lac-Z reporter mouse lines, we report that VEGF is produced by various cells in the adult mouse retina and that VEGFR2, the primary signaling receptor, is also widely expressed, with strong expression by Müller cells and photoreceptors. Systemic neutralization of VEGF was accomplished in mice by adenoviral expression of sFlt1. After 14 days of VEGF neutralization, there was no effect on the inner and outer retina vasculature, but a significant increase in apoptosis of cells in the inner and outer nuclear layers. By four weeks, the increase in neural cell death was associated with reduced thickness of the inner and outer nuclear layers and a decline in retinal function as measured by electroretinograms. siRNA-based suppression of VEGF expression in a Müller cell line in vitro supports the existence of an autocrine role for VEGF in Müller cell survival. Similarly, the addition of exogenous VEGF to freshly isolated photoreceptor cells and outer-nuclear-layer explants demonstrated VEGF to be highly neuroprotective. These results indicate an important role for endogenous VEGF in the maintenance and function of adult retina neuronal cells and indicate that anti-VEGF therapies should be administered with caution.
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