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A Novel Model of Retinopathy of Prematurity Simulating Preterm Oxygen Variability in the Rat

¹ From the Child Life and Health, Reproductive and Developmental Sciences, University of Edinburgh; and ² Princess Alexandra Eye Pavilion, Edinburgh, Scotland, United Kingdom.

PURPOSE. To examine changes in the retinal vasculature of rat pups after 14 days of minute-by-minute small variations in oxygen.

METHODS. Arterial oxygen data from a preterm infant who developed severe retinopathy of prematurity (ROP) was translated to equivalent values for the rat. Newborn rat pups were raised for 14 days in a cage in which a computer controlled the atmosphere to mimic the fluctuating oxygen profile (group V). Positive controls (P) of 12-hour cycles of 80% and 21% were run concurrently, as were room air controls (C). All were killed at day 14.

RESULTS. Groups V and P had significantly larger avascular retinal areas than C [median, interquartile range (IQR): 1.7%, 0–7.9%; 10%, 8.1–13%; 0%, 0–0%, respectively; each group n = 30]. Group P had a higher capillary branch count than C (median, IQR: 310/mm²; 253–311 mm²; versus 277/mm², 272–364/mm², respectively), but this was not significant using a multilevel analysis. Group V had significantly reduced capillary counts compared with C (median, 261/mm²; IQR, 215–290/mm²; P < 0.05 multilevel analysis). No neovascularization was seen in any group, though abnormal terminal vessels were seen at the avascular/vascular retina interface in 73% of rats in group P and 21% of rats in group V. In situ hybridization on serial sections demonstrated VEGF in the inner nuclear layer of the retina in P and V, whereas C showed trace levels only.

CONCLUSIONS. The vaso-obliterative stage of ROP can be induced in rats using clinically relevant oxygen levels.

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