Objective: To determine the effects of oxygen fluctuations on pigment epithelial-derived factor (PEDF) and vascular endothelial growth factor (VEGF)/PEDF ratios in a relevant rat model of retinopathy of prematurity (ROP).
Methods: The expression of retinal PEDF mRNA and of VEGF and PEDF protein were determined using real-time polymerase chain reaction or enzyme-linked immunosorbent assays at different postnatal day ages for rat pups raised in room air (RA) or in a rat model mimicking ROP. Statistical outcomes were determined with factorial analyses of variance. Mean VEGF and PEDF protein levels were determined at different ages for rats in the ROP model and for RA-raised rats, and the ratio of VEGF/PEDF protein versus age was plotted. At postnatal day (P) 14, inner retinal plexus vascularization had extended to the ora serrata in pups raised in RA. In the ROP model, avascular retina persisted at P14 and intravitreous neovascularization developed at P18. Therefore, VEGF and PEDF expression was determined in the ROP model and in RA-raised rat pups at P14 and P18.
Results: Older age was associated with increased PEDF mRNA (p<0.001), PEDF protein (p=0.005), and VEGF protein (p=0.005), and VEGF protein (p<0.0001). Exposure to fluctuations of oxygen in the 50/10 oxygen-induced retinopathy model compared to RA was associated with increased PEDF mRNA (p=0.0185), PEDF protein (p<0.0001), or VEGF protein (p<0.0001). The VEGF/PEDF ratio favored angiogenic inhibition (<1.0) before but not on P14, when avascular retina persisted in the ROP model but not in RA. The VEGF/PEDF ratio favored angiogenesis (>1.0) at P14 and P 18 when intravitreous neovascularization occurred in the ROP model.
Conclusions: Increased expression levels of VEGF and PEDF are associated with older postnatal day age or with exposure to fluctuations in oxygen in the 50/10 oxygen-induced retinopathy model compared to RA. PEDF protein more closely associates with avascular retinal features and neovascularization than does VEGF protein or the VEGF/PEDF in the ROP model. Although PEDF has been proposed as a potential treatment in ROP, interventional studies using PEDF in an ROP model to potentially reduce intravitreous neovascularization are required to determine timing, efficacy, and dose of PEDF.