As the response of the adult retina to hypoxia is likely to differ from that already established in the neonatal animal, this study was undertaken to examine the expression patterns of insulin-like growth factor-I (IGF-I) and -II (IGF-II), angiopoietin-2 (Ang-2), and pigment epithelium-derived growth factor (PEDF) in normal and hypoxic retinas of adult rats. In the latter, the retinas were examined from 3 hr to 14 days after hypoxic exposure. The mRNA and protein expression of IGF-I, IGF-II, Ang-2, and PEDF in the retina was determined by real-time RT-PCR, Western blotting, and immunohistochemistry. The results showed up-regulated expression of IGF-I, IGF-II, and Ang-2 mRNA and protein in response to hypoxia, whereas PEDF expression was drastically reduced, suggesting that increased expression of IGF-I and IGF-II may be involved not only in neovascularization but also in neuroprotection in hypoxic conditions. The up-regulation of Ang-2, a proangiogenic factor, and the down-regulation of PEDF, an antiangiogenic factor, is indicative of an imbalance between pro- and antiangiogenic factors in the hypoxic retina that may favor neovascularization. This was supported by the increased density of rat endothelial cell antigen-1 (RECA-1) protein quantification and RECA-1-stained blood vessels in the inner retina.