Abstract
Purpose: :
Supplemental oxygen administration, which is frequently encountered in the treatment of premature infants suffering from respiratory distress, contributes to the development of retinopathy of prematurity (ROP). The purpose of this study was to test the hypothesis that neonatal exposure of rats to a combination of all–trans retinoic acid (RA) and hyperoxia would alleviate retinopathy and abnormal neovascularization compared to those exposed to hyperoxia alone.
Methods: :
Newborn Fisher 344 rats were maintained in room air or exposed to hyperoxia ([gt] than 95% O2) for 7 days. Some animals were treated i.p. with RA (0.5 mg/kg) or vehicle (saline), once daily for the first 5 days of hyperoxic exposures. Animals were sacrificed at selected time points after termination of hyperoxia. Retinal histopathology and vascular densities of flat mounted retinas were assessed. mRNA expression of VEGF and its receptors (VEGFR1 and VEGFR2), and HIF–1alpha was determined by real time RT–PCR.
Results: :
Immediately after 7 days of exposure to hyperoxia alone or to hyperoxia + RA, we observed constricted retinal vessels, compared to air breathing animals. Seven to thirty days after termination of hyperoxia, the animals displayed formation of abnormal retinal vessels and capillaries, whereas animals given RA+ hyperoxia showed significantly lesser extent of neovascularization. At these time points, VEGF mRNA expression in the hyperoxia group was much higher than that of the RA+ hyperoxia group. On the other hand, expression of VEGFR1and HIF–1alpha, but not VEGR2, was augmented by RA + hyperoxia, compared to those animals exposed to oxygen alone.
Conclusions: :
Our study supports the hypothesis that RA protects retinas from oxygen–induced retinopathy with abnormal neovascularization, and that modulation of expression of VEGF and its receptors via HIF–1alpha contributes to the retinoprotective effects of RA. These results encourage development of further studies to elucidate molecular mechanisms of RA action and clinical trials in infants at risk of developing ROP.
Keywords: retinopathy of prematurity • retinoids/retinoid binding proteins • retinal neovascularization