There is a delicate balance between angiogenic stimulators and angiogenic inhibitors that regulates angiogenesis in the retina. Under certain pathological conditions, this balance is broken in response to local ischemia, which results in neovascularization. Recently, we have measured the vascular endothelial growth factor (VEGF)/PEDF ratio as a representative of the balance and correlated it with retinal neovascularization. In rat retinas with neovascularization, VEGF increased by fivefold over the age-matched controls, whereas PEDF decreased to approximately half of the control level, resulting in an increased VEGF/PEDF ratio. The time course of the ratio change was consistent with the progression of retinal neovascularization. We have also correlated susceptibilities to retinal neovascularization with the VEGF/PEDF ratio change in response to ischemia in Sprague Dawley (SD) and brown Norway (BN) rats. An exposure to constant hyperoxia followed by normoxia-induced significant retinal neovascularization in BN rats, but not in SD rats, suggests that BN rats are more susceptible to retinal neovascularization than SD rats. Consistent with this observation, the hyperoxia-treated BN rats showed a significant reduction in retinal PEDF but a substantial increase of VEGF at both the protein and RNA levels, resulting in a dramatically increased VEGF/PEDF ratio. In contrast, hyperoxia-treated SD rats showed fewer and shorter changes in PEDF and VEGF levels than BN rats. In age-matched normal BN and SD rats, however, there was no detectable difference in the basal VEGF/PEDF ratio between the strains. These results support the idea that different regulations of angiogenic inhibitors and stimulators under ischemia are responsible for the differences in susceptibility to ischemia-induced retinal neovascularization in SD and BN rats. Previously, we have shown that plasminogen kringle 5 (K5), a known angiogenic inhibitor, inhibited the proliferation of primary retinal capillary endothelial cells and inhibited retinal neovascularization in the BN rat model. Interestingly, K5 also downregulated VEGF expression but upregulated PEDF expression in both the cultured cells and rat retinas, suggesting that the antiangiogenic activity of K5 may be through decreasing the VEGF/PEDF ratio. These observations suggest that the balance between angiogenic stimulators and inhibitors plays a crucial role in the development of retinal neovascularization.