The vascular endothelial growth factor (VEGF) family of growth factors controls pathological angiogenesis and increased vascular permeability in important eye diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). The purpose of this review is to develop new insights into the cell biology of VEGFs and vascular cells in angiogenesis and vascular leakage in general, and to provide the rationale and possible pitfalls of inhibition of VEGFs as a therapy for ocular disease. From the literature it is clear that overexpression of VEGFs and their receptors VEGFR-1, VEGFR-2 and VEGFR-3 is causing increased microvascular permeability and angiogenesis in eye conditions such as DR and AMD. When we focus on the VEGF receptors, recent findings suggest a role of VEGFR-1 as a functional receptor for placenta growth factor (PlGF) and vascular endothelial growth factor-A (VEGF)-A in pericytes and vascular smooth muscle cells in vivo rather than in endothelial cells, and strongly suggest involvement of pericytes in early phases of angiogenesis. In addition, the evidence pointing to distinct functions of VEGFs in physiology in and outside the vasculature is reviewed. The cellular distribution of VEGFR-1, VEGFR-2 and VEGFR-3 suggests various specific functions of the VEGF family in normal retina, both in the retinal vasculature and in neuronal elements. Furthermore, we focus on recent findings that VEGFs secreted by epithelia, including the retinal pigment epithelium (RPE), are likely to mediate paracrine vascular survival signals for adjacent endothelia. In the choroid, derailment of this paracrine relation and overexpression of VEGF-A by RPE may explain the pathogenesis of subretinal neovascularisation in AMD. On the other hand, this paracrine relation and other physiological functions of VEGFs may be endangered by therapeutic VEGF inhibition, as is currently used in several clinical trials in DR and AMD.

中文翻译：

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眼部疾病中的血管内皮生长因子和血管生成。

血管内皮生长因子（VEGF）家族的生长因子可控制重要的眼部疾病（如糖尿病性视网膜病变（DR）和年龄相关性黄斑变性（AMD））的病理性血管生成和增加的血管通透性。这篇综述的目的是发展对血管生成和血管渗漏中的VEGF和血管细胞的细胞生物学的新见解，并提供抑制VEGF作为眼病治疗的原理和可能的陷阱。从文献中可以明显看出，VEGF及其受体VEGFR-1，VEGFR-2和VEGFR-3的过度表达在诸如DR和AMD的眼部疾病中引起微血管通透性增加和血管生成。当我们专注于VEGF受体时，最近的发现表明，VEGFR-1作为胎盘生长因子（PlGF）和血管内皮生长因子-A（VEGF）-A的功能性受体，在体内而非在内皮细胞中在周细胞和血管平滑肌细胞中的作用，并强烈暗示周细胞参与血管生成的早期阶段。另外，综述了指向VEGF在脉管系统内外的生理学中的独特功能的证据。VEGFR-1，VEGFR-2和VEGFR-3的细胞分布表明，正常视网膜中的VEGF家族在视网膜脉管系统和神经元中都有各种特定功能。此外，我们关注于最近的发现，即包括视网膜色素上皮（RPE）在内的上皮分泌的VEGF可能介导相邻内皮的旁分泌血管存活信号。在脉络膜中 RPE的这种旁分泌关系的脱轨和VEGF-A的过表达可能解释了AMD视网膜下新血管形成的发病机理。另一方面，VEGF的这种旁分泌关系和其他生理功能可能受到治疗性VEGF抑制的威胁，如目前在DR和AMD中的一些临床试验中所使用的。