Ischemic retinopathies causing overexpression of pro-angiogenic factors, including vascular endothelial growth factor (VEGF), are the most common cause of blindness. Thus, understanding the pathophysiology of targetable pathways that regulate retinal VEGF is of great interest. A conserved binding site for estrogen-related receptor gamma (ERR gamma) has been identified in the promoter of the Vegfa gene. ERR gamma is a constitutively active orphan nuclear receptor and its expression is increased by hypoxic stimuli in metabolically active tissues. This study evaluated the role of ERR gamma in the ischemic retina and the antiVEGF potential of GSK5182, a selective inverse agonist of ERR gamma. In an oxygen-induced retinopathy (OIR) mouse model, immunohistochemistry showed significantly increased ERR gamma expression in the ganglion cell layer at postnatal day (P) 17. In a ganglion cell line (RGC-5), mRNA and protein levels of ERR gamma were increased by desferrioxamine treatment and hypoxic conditions (1% O-2). Transient transfection of RGC-5 cells revealed that ERR gamma regulated Vegfa expression and this was inhibited by GSK5182. Intravitreal injection of GSK5182 into the OIR model at P14 inhibited retinal Vegfa mRNA expression at P17. GSK5182 suppresses hypoxia-induced VEGF expression via ERR gamma; therefore, ERR gamma could be a treatment target for ischemic retinopathies. (C) 2015 Elsevier Inc. All rights reserved.