REGULATION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR BY OXYGEN IN A MODELOF RETINOPATHY OF PREMATURITY

Objectives: To investigate the role of vascular endothelial growth fac tor (VEGF) in the pathogenesis of the first phase of retinopathy of pr ematurity (ROP) and to examine the mechanism by which supplemental oxy gen therapy might inhibit neovascularization in the second phase of RO P. Methods: A novel combination of fluorescein-dextran perfusion and c olorimetric whole-retina in situ hybridization was used to evaluate th e expression of VEGF messenger RNA in relationship to the location of blood vessels in retinas from neonatal mice that were exposed to hyper oxia. Northern blot and immunoblot analyses were used to quantify the changes in VEGF messenger RNA and protein expression caused by hyperox ia. The ability of VEGF to prevent hyperoxia-induced vaso-obliteration was evaluated by injecting exogenous VEGF into the vitreous cavity pr ior to oxygen exposure. Results: Vascular endothelial growth factor me ssenger RNA was produced in a reticular pattern just anterior to the d eveloping blood vessels in normal retina on postnatal day 7. The expre ssion of VEGF in the peripheral retina was down-regulated by hyperoxia in conjunction with the arrest of growth and the loss of some of the developing vasculature. Total VEGF messenger RNA and protein levels in retinas from animals on postnatal day 7 were decreased 55% and 85%, r espectively, after 6 hours in 75% oxygen. Vase-obliteration was inhibi ted 57% by pretreatment of animals with exogenous VEGF. In animals wit h retinal ischemia secondary to loss of vasculature, treatment with su pplemental oxygen therapy decreased stimulated retinal VEGF levels by approximately 70%. Conclusions: Down-regulation of VEGF expression by hyperoxia may be partly responsible for the vaso-obliteration and cess ation of normal retinal blood vessel growth observed in premature infa nts in whom ROP develops. Hyperoxia also has the potential to be used therapeutically to down-regulate VEGF expression in hypoxic retina in the hope of limiting the neovascular complications of ROP. Based on th ese findings about the regulation of VEGF expression in the retina, an explanation of the pathogenesis of ROP is proposed.