Extraretinal neovascularization induced by hypoxic episodes in the neonatal rat

To test the hypothesis that hypoxia induces retinal neovascularization. To produce relative hypoxia in the avascular retina, newborn rats were exposed for 11 days to 80% oxygen interrupted daily by short episodes in room air. Episodes in room air lasted 1/2 hour or 1 hour followed by abrupt reintroduction, or 1/2 hour followed by progressive reintroduction to 80% oxygen lasting 3 hours to prolong the period of hypoxia. At the end of the 11 days of interrupted oxygen exposure, the animals were left in room air for 6 days. The incidence of neovascularization exhibited a dose-response relationship to the period out of 80% oxygen. Periods of approximately 3 hours produced neovascularization (in at least one eye) in 94% of the animals. The total area of the peripheral avascular retina was larger in animals exposed to prolonged periods of hypoxia than in those exposed for shorter periods. The incidence of neovascularization was strongly associated with the total area of the peripheral avascular retina and occurred in the inferior quadrant in 78% of the cases. Additional features of stage 3 retinopathy of prematurity (ROP), including arteriovenous shunts and ridges, were observed in some retinas. These data demonstrate that hypoxic episodes can induce extraretinal neovascularization in the rat and suggest that brief periods of oxygen deficiency could exacerbate progression of ROP. With the high incidence and predictability of localization of neovascularization, this model could be useful for the study of angiogenesis and for evaluation of antiangiogenic or antioxidant substances.