Abstract
Retinopathy of prematurity (ROP) and diabetic retinopathy (DR) are ocular disorders in which a loss of retinal vasculature leads to ischemia followed by a compensatory neovascularization response. In mice, this is modeled using oxygen-induced retinopathy (OIR), whereby neonatal animals are transiently housed under hyperoxic conditions that result in central retina vessel regression and subsequent neovascularization. Using endothelial cell (EC)-specific gene deletion, we found that loss of two ETS-family transcription factors, ERG and FLI1, led to regression of OIR-induced neovascular vessels but failed to improve visual function, suggesting that relevant retinal damage occurs prior to and independently of neovascularization. Turning our attention to the initial stage of OIR, we found that hyperoxia repressed ERG expression in retinal ECs of wild type mice, raising the possibility that oxygen-induced ERG downregulation promotes vessel regression during the initiation of OIR-induced pathology. We therefore developed a murine model of EC-specific ERG overexpression and found it sufficient to prevent hyperoxia-induced vascular regression, neuronal cell death, and neovascularization in the OIR model. Importantly, ERG overexpression also improved visual function in OIR-challenged mice. Moreover, we show that both ERG and FLI1 are downregulated in the retinal vessels of human patients with early stages of DR, suggesting that neovascular disorders of the eye may share common mechanisms underlying pathological retinal capillary regression. Collectively, these data suggest that the regulation of vascular regression by EC-expressed ETS transcription factors may be adapted towards novel therapeutic approaches for the prevention and/or alleviation of ocular neovascular disorders.