EVIDENCE FOR UP-REGULATION AND REDISTRIBUTION OF VASCULAR ENDOTHELIALGROWTH-FACTOR (VEGF) RECEPTORS FLT-1 AND FLK-1 IN THE OXYGEN-INJURED RAT RETINA

There is considerable evidence that vascular endothelial growth factor (VEGF) is important in the pathogenesis of retinal neovascular diseas es, The effects of this endothelial cell-specific mitogen are mediated by specific cell surface receptors, In this study me probed for the t wo VEGF receptors (VEGFRs) known to have highest affinity in the rat - flt-1 and flk-1, Using a well-characterized rat model of the neovascu lar disease retinopathy of prematurity (ROP), we performed immunohisto chemical assays on methacrylate sections of eyes from normal and oxyge n-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 the re was light, diffuse labeling of the inner nuclear layer and outer pl exiform layer. In contrast, in 4 of 5 oxygen-injured eyes on day 16, t here was specific labeling of small neovascular growths and normal ret inal vessels, and the outermost (sclerad) limit of the label had shift ed inward to the vitread border of the inner nuclear layer and the inn er plexiform layer, Day 20 room air eyes showed a pattern similar to d ay 16, although with stronger labeling. However, in oxygen-injured eye s on day 20 the labeling pattern had shifted toward the vitreous, with extremely strong labeling of the preretinal neovascular growths, As o n 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 i mmunolabels revealed overlap and strong similarity on day 20 in the ox ygen-injured eyes, This is the first report of VEGF receptor protein b eing concentrated in preretinal neovascular growths in a model of ROP, These results lend themselves to further investigation of the roles o f VEGFRs in preretinal neovascularization in ROP and other retinal dis eases and suggest avenues of research toward therapies using VEGFR ant agonists.