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Updated: Jul 13, 2026
Oxygen-Induced Retinopathy Model for Ischemic Retinal Diseases in Rodents
Published on: September 16, 2020
Kinetics of strain-dependent differential gene expression in oxygen-induced retinopathy in the rat
Peter van Wijngaarden1, Helen M Brereton, Ian L Gibbins
1Department of Ophthalmology, Flinders University of South Australia, Flinders Medical Centre, Bedford Park, Adelaide, SA 5042, Australia. vanw0009@flinders.edu.au
Insights
Genetic differences in rats influence susceptibility to oxygen-induced retinopathy (OIR). Early in development, resistant rats show higher angiogenesis gene expression, which reverses during OIR
Area of Science:
- Ophthalmology
- Genetics
- Molecular Biology
Background:
- Retinopathy of prematurity (ROP) is a potentially blinding condition in premature infants.
- Genetic factors contribute to ROP susceptibility.
- Oxygen-induced retinopathy (OIR) in rats is a model for studying ROP.
Purpose of the Study:
- To investigate the genetic basis of differential susceptibility to OIR in inbred rat strains.
- To quantify retinal expression of angiogenesis-related genes in OIR-susceptible and OIR-resistant rats.
Main Methods:
- Inbred Fischer 344 (F344), Dark Agouti (DA), and Sprague Dawley (SPD) rat neonates were subjected to cyclic hyperoxia (80% oxygen) for up to 14 days.
- Retinal mRNA expression of 8 angiogenesis-related genes (VEGF, VEGFR2, PEDF, Ang2, Tie2, COX2, IGF1, EPO) was quantified using real-time RT-PCR at various time points.
- Gene expression patterns were analyzed in OIR-resistant (F344) versus OIR-susceptible (DA, SPD) rat strains.
Main Results:
- During early development (first 9 days) under cyclic hyperoxia, OIR-resistant F344 rats showed significantly higher retinal mRNA expression of VEGF, VEGFR2, and Ang2 compared to OIR-susceptible DA rats.
- At later time points (post-natal days 14 and 18), OIR-susceptible DA and SPD rats exhibited significantly greater retinal mRNA expression of VEGF, EPO, VEGFR2, Ang2, IGF1, COX2, and PEDF than OIR-resistant F344 rats.
- The VEGF/PEDF ratio was higher in F344 rats up to day 9 but shifted to be higher in DA rats at days 14 and 18, indicating a dynamic change in angiogenic balance.
Conclusions:
- Susceptibility to OIR in rats is associated with differential expression of angiogenesis-related genes.
- Gene expression patterns differ significantly between OIR-resistant and OIR-susceptible strains during early retinal microvascular development.
- The reversal of gene expression patterns during the proliferative phase of OIR suggests distinct molecular mechanisms underlying susceptibility.
Abstract:
Recent evidence suggests that retinopathy of prematurity, a potentially blinding condition of premature human neonates, has a genetically-determined component. Different inbred strains of rat exhibit differential susceptibility to oxygen-induced retinopathy (OIR), a well-established experimental model of retinopathy of prematurity. To explore the basis for this differential susceptibility, we quantified the retinal expression of 8 angiogenesis-related genes during early post-natal retinal development in rats with OIR. Inbred Fischer 344 (F344), Dark Agouti (DA) and Sprague Dawley (SPD) rat neonates were exposed to alternating cycles of 80% oxygen in air and normoxia for up to 14 days. After 14 days of cyclic hyperoxic exposure, some rats were exposed to normoxia for a further 4 days. Retinal mRNA for vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2), pigment epithelium-derived factor (PEDF), angiopoietin-2 (Ang2), Tie2, cyclooxygenase-2 (COX2), insulin-like growth factor-1 (IGF1) and erythropoietin (EPO) were quantified by real-time reverse-transcriptase polymerase chain reaction at different time-points. Time-course analysis showed that expression of mRNA for VEGF, VEGFR2 and Ang2 was significantly greater in OIR-resistant (F344) retinae than in OIR-susceptible (DA) retinae during the first 9 days of cyclic hyperoxia. However, at post-natal days 14 and 18, retinal mRNAs for VEGF, EPO, VEGFR2, Ang2, IGF1, COX2 and PEDF were expressed to a significantly greater extent in OIR-susceptible (DA, SPD) than OIR-resistant (F344) retinae. The VEGF/PEDF ratio was greater in the F344 compared with the DA strain up to day 9, but was higher in the DA than the F344 strain at days 14 and 18. Thus, we found that retinal expression of angiogenesis-related genes was significantly higher in OIR-resistant rats than in OIR-susceptible rats during early retinal development, but the pattern reversed during the proliferative phase of OIR. We conclude that susceptibility to OIR correlates with differential gene expression very early in retinal microvascular development, during periods of cyclic hyperoxic exposure rather than during subsequent sustained hypoxia.
