Robbins S G, Rajaratnam V S, Penn J S
Arkansas Center for Eye Research, Jones Eye Institute, University of Arkansas for Medical Sciences, Little Rock 72205, USA.
Growth Factors. 1998;16(1):1-9. doi: 10.3109/08977199809017487.
There is considerable evidence that vascular endothelial growth factor (VEGF) is important in the pathogenesis of retinal neovascular diseases. The effects of this endothelial cell-specific mitogen are mediated by specific cell surface receptors. In this study we probed for the two VEGF receptors (VEGFRs) known to have highest affinity in the rat--flt-1 and flk-1. Using a well-characterized rat model of the neovascular disease retinopathy of prematurity (ROP), we performed immunohistochemical assays on methacrylate sections of eyes from normal and oxygen-injured animals at the time neovascularization is first observed (16 days of age) and at its peak (day 20). In day 16 room air retinas there was light, diffuse labeling of the inner nuclear layer and outer plexiform layer. In contrast, in 4 of 5 oxygen-injured eyes on day 16, there was specific labeling of small neovascular growths and normal retinal vessels, and the outermost (sclerad) limit of the label had shifted inward to the vitread border of the inner nuclear layer and the inner plexiform layer. Day 20 room air eyes showed a pattern similar to day 16, although with stronger labeling. However, in oxygen-injured eyes on day 20 the labeling pattern had shifted toward the vitreous, with extremely strong labeling of the preretinal neovascular growths. As on day 16 there was also labeling of the inner plexiform layer and the inner portion of the inner nuclear layer, but not the outer plexiform layer. Comparison of VEGF protein immunolabel with both of the VEGFR immunolabels revealed overlap and strong similarity on day 20 in the oxygen-injured eyes. This is the first report of VEGF receptor protein being concentrated in preretinal neovascular growths in a model of ROP. These results lend themselves to further investigation of the roles of VEGFRs in preretinal neovascularization in ROP and other retinal diseases and suggest avenues of research toward therapies using VEGFR antagonists.
有大量证据表明血管内皮生长因子（VEGF）在视网膜新生血管疾病的发病机制中起重要作用。这种内皮细胞特异性促有丝分裂原的作用是由特定的细胞表面受体介导的。在本研究中，我们探究了已知在大鼠中具有最高亲和力的两种VEGF受体（VEGFRs）——flt-1和flk-1。使用一种特征明确的早产儿视网膜病变（ROP）新生血管疾病大鼠模型，我们在首次观察到新生血管形成时（16日龄）和高峰期（20日龄），对正常和氧损伤动物眼睛的甲基丙烯酸酯切片进行了免疫组织化学分析。在16日龄的空气中饲养的视网膜中，内核层和外网状层有轻度、弥漫性标记。相比之下，在16日龄的5只氧损伤眼中，有4只眼中的小新生血管生长和正常视网膜血管有特异性标记，并且标记的最外层（巩膜侧）界限已向内转移到内核层和内网状层的玻璃体边界。20日龄的空气中饲养的眼睛显示出与16日龄相似的模式，尽管标记更强。然而，在20日龄的氧损伤眼中，标记模式已向玻璃体方向转移，视网膜前新生血管生长有极强的标记。与16日龄时一样，内网状层和内核层内部也有标记，但外网状层没有。VEGF蛋白免疫标记与两种VEGFR免疫标记的比较显示，在20日龄的氧损伤眼中存在重叠和高度相似性。这是关于VEGF受体蛋白在ROP模型的视网膜前新生血管生长中集中分布的首次报道。这些结果有助于进一步研究VEGFRs在ROP和其他视网膜疾病的视网膜前新生血管形成中的作用，并为使用VEGFR拮抗剂的治疗研究提供途径。
