The role of VEGF and IGF-1 in a hypercarbic oxygen-induced retinopathy rat model of ROP

PURPOSE: We have previously described a severe form of oxygen-induced retinopathy (OIR) in the neonatal rat, analogous to human retinopathy of prematurity (ROP), where carbon dioxide is added to the inspired environment (hypercarbic OIR). We studied the time course of emergence and resolution of neovascularization (NV) in normocarbic OIR and hypercarbic OIR and the associated changes in VEGF and IGF-1 mRNA levels in hypercarbic OIR. METHODS: 550 newborn Sprague-Dawley rats were raised in 22 expanded litters of 25. Beginning at day 1 of life, rats were exposed to 7 daily cycles of hyperoxia (80% O2, 20.5 h) and hypoxia (10% O2, 0.5 h) with a gradual return to 80% O2 over 3 h. Inspired CO2 was maintained at 0.2% for 200 rats (normocarbic OIR) and 10% for 100 rats (hypercarbic OIR). Rats were sacrificed after a subsequent 5 day room air recovery period. An additional 250 rats raised in room air served as age matched controls. Retinae from left eyes were dissected and flatmounts were ADPase-stained. The presence and severity of NV was scored in a masked manner. Right eyes in hypercarbic OIR litters and room air controls were processed for analysis of VEGF and IGF-1 mRNA. RESULTS: In normocarbic OIR, NV started to emerge before room air recovery began at day 8. It was maximal at day 10 and resolved by day 20. In hypercarbic OIR, a similar pattern was seen, with emergence prior to day 8, peak at day 13 and resolution by day 20. In hypercarbic OIR, retinal VEGF mRNA was decreased at day 8 and increased at day 10 compared to room air controls, correlating with maximal NV. Retinal IGF-1 mRNA was not increased at any time in hypercarbic OIR compared to room air controls. CONCLUSIONS: Neovascularization resulting from normocarbic OIR or hypercarbic OIR occurs before room air recovery. Retinal VEGF mRNA was downregulated and subsequently upregulated prior to maximal NV in hypercarbic OIR. Neovascularization in the hypercarbic OIR model does not appear to be associated with increased retinal IGF-1 mRNA.