Novel short-term and long-term clinical changes in a mouse model of hyperoxia-induced retinopathy and hyperplastic vitreous

Abstract

Purpose: The incidence of retinopathy of prematurity (ROP) has increased globally due to advances in the care of very low weight premature infants. Neonates are now viable at earlier time points than was possible 20-30 years ago. In this context we sought to determine the short-term and long-term effects of earlier neonatal exposure to clinically relevant levels of oxygen (O₂) than in the traditional mouse model of ROP.

Methods: Neonatal C57BL/6J mice were raised in hyperoxic conditions (40% or 65% O₂) from birth until postnatal day 7 (D0-D7) and then raised in normoxia until early adulthood (8 week old) or middle-age (40 week old). Control animals were raised in normoxia throughout the experiment. Brightfield fundus imaging and fluorescein angiography (Micron III) was performed at 8 and 40 weeks.

Results: In vivo fundus examination revealed multiple retinal lesions and abnormal retinal and hyaloid vasculature. In animals exposed to 65% O₂ we noted retinal vascular changes including hyperplasia, calibre changes (thinning) and increased tortuosity as well as persistent hyperplastic hyaloid vessels at 8 and 40 weeks of age. The average number of hyaloid vessels present in animals exposed to 65% O₂ is significantly higher than normal (0.77±0.35), at both 8 weeks (5.45±0.37) and 40 weeks (4.9±0.17). Exposure to 40% O₂ from D0-D7 caused altered retinal vasculature patterns but no retinal lesions were observed. Fundus appearance at 8 weeks was normal in animals exposed to normoxia.

Conclusions: The results demonstrated that neonatal exposure to 65% O₂ produced marked clinical retinal changes that bore strong resemblance to some aspect of human ROP. This earlier exposure (D0-D7) to hyperoxia than the traditional model of ROP (D5-D12) also caused persistent hyperplastic hyaloid vasculature. To our knowledge the long term follow up of mice using this earlier exposure period to hyperoxia has not been reported previously and may be particularly relevant in an era where infants are surviving birth at earlier gestational ages.

Keywords: 706 retinopathy of prematurity • 635 oxygen • 700 retinal neovascularization