Abstract
PURPOSE: The adenosine A(2A) receptor (A(2A)R) modulates normal vascularization and pathologic angiogenesis in many tissues and may contribute to the pathogenesis of retinopathy of prematurity (ROP) characterized by abnormal retinal vascularization in surviving premature infants. Here, the authors studied the effects of the genetic inactivation of A(2A)R on normal retinal vascularization and the development of pathologic angiogenesis in oxygen-induced retinopathy (OIR), an animal model of ROP. METHODS: After exposure to 75% oxygen for 5 days (postnatal day [P] 7-P12) and subsequently to room air for the next 9 days (P13-P21), we evaluated retinal vascular morphology by ADPase staining in retinal whole mounts, retinal neovascularization response by histochemistry in serial retinal sections, and retinal VEGF gene expression by real-time PCR analysis in A(2A)R knockout (KO) mice and their wild-type (WT) littermates. RESULTS: At P17, A(2A)R KO mice displayed attenuated OIR compared with WT littermates, as evidenced by reduced vaso-obliteration and areas of nonperfusion in the center of the retina, reduced pathologic angiogenesis as evident by decreased non-ganglion cells and neovascular nuclei, and inhibited hypoxia-induced retinal VEGF gene expression. Notably, the attenuation of pathologic angiogenesis by A(2A)R inactivation was selective for OIR because it did not affect normal retinal vascularization during postnatal development. CONCLUSIONS: These findings provide the first evidence that A(2A)R is critical for the development of OIR and suggest a novel therapeutic approach of A(2A)R inactivation for ROP by selectively targeting pathologic but not developmental angiogenesis in the retina.