Kinetics of strain-dependent differential gene expression in oxygen-induced retinopathy in the rat.
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.
van Wijngaarden
Peter
P
Department of Ophthalmology, Flinders University of South Australia, Flinders Medical Centre, Bedford Park, Adelaide, SA 5042, Australia. vanw0009@flinders.edu.au
Brereton
Helen M
HM
Gibbins
Ian L
IL
Coster
Douglas J
DJ
Williams
Keryn A
KA
D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D006801:Humans; D007231:Infant, Newborn; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000096:biosynthesis / Q000235:genetics; D010100:Oxygen / Q000494:pharmacology / Q000633:toxicity; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011919:Rats, Inbred Strains; D012160:Retina / Q000378:metabolism; D012178:Retinopathy of Prematurity / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015843:Serpins / Q000096:biosynthesis / Q000235:genetics; D013045:Species Specificity; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics; D000099174:Pigment Epithelium-Derived Factor
D043925:Angiogenesis Inducing Agents; D005136:Eye Proteins; D009414:Nerve Growth Factors; D010100:Oxygen; D012333:RNA, Messenger; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A; D000099174:Pigment Epithelium-Derived Factor