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J. S. Hartmann, W. Huang, S. J. Budd, K. Barton, A. Richardson, M. E. Hartnett; Modulation of Vascular Endothelial Growth Factor and Pigment Epithelial-Derived Factor Signaling by Alternating Periods of Hyperoxia and Hypoxia in a Relevant Model of Retinopathy of Prematurity. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4467.
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© ARVO (1962-2015); The Authors (2016-present)
To determine the effects of oxygen fluctuations on PEDF and the VEGF/PEDF ratio during development and in a relevant model of retinopathy of prematurity (ROP).
Upon four hours of birth, Sprague-Dawley rat pups and their mothers were exposed to 24 hour cycles of alternating 50% oxygen and 10% oxygen until postnatal day (p)14, at which time they were placed into room air (ROP model). Control litters were raised in a room air environment. Rat pups from the ROP model and age-matched controls were sacrificed at time points p0, p8, p11, p12, p13, p14, and p18. Real-time PCR was used to determine mRNA expressions of VEGF splice variants (VEGF188, VEGF120, VEGF164) and PEDF using β-actin as a control gene. VEGF and PEDF protein were measured with commercially-available ELISAs. The ratios of fold change in expression of each splice variant to fold change of PEDF were determined in both room air and the ROP model at each time point. Then, a ratio of ROP/room air was determined for each time point and splice variant analyzed. A similar VEGF/PEDF ratio was determined for protein.
At p14, development of the retinal vasculature was incomplete in the ROP model, whereas vascularization of the inner plexus was complete in room air pups. The ratio of the most prevalent splice variant (VEGF164) to PEDF was less than 1.0 prior to p12, but greater than 1.0 after p12. At p18, the time point corresponding to maximal intravitreous neovascularization, the VEGF/PEDF ratio was greater than 1.0 for all splice variants. In the ROP model, PEDF protein was significantly elevated compared to room air at most time points before p18 (p=0.046 at p8, p = 0.002 at p11, p=0.0001 at p12, p=0.001 at p14). Furthermore, the VEGF/PEDF ratio for protein was greater than 1.0 at time points p14 and p18.
Repeated fluctuations in oxygen, a risk factor for severe ROP, was associated with increased expression of VEGF and PEDF compared to age-matched room air pups. At time points when avascular retina was present in the ROP model but not in room air and when intravitreous neovascularization was present, the VEGF/PEDF ratio was greater than 1.0. VEGF/PEDF ratios greater than 1.0 may reflect a pro-angiogenic environment and were present both at p14 and p18 in the ROP model.
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