Hypoxic retinal Müller cells promote vascular permeability by HIF-1–dependent up-regulation of angiopoietin-like 4

Significance Ischemic retinopathies include a diverse group of diseases in which immature retinal vasculature or damage to mature retinal vessels leads to retinal ischemia. The anticipated rise in the worldwide prevalence of diabetes will result in a concurrent increase in the number of patients with vision impairment from diabetic eye disease, the most common cause of ischemic retinopathy. We set out to identify novel hypoxia-inducible genes that promote vascular permeability and may therefore play a role in the pathogenesis of diabetic eye disease. We demonstrate that angiopoietin-like 4 (ANGPTL4) is up-regulated by the transcriptional enhancer, hypoxia-inducible factor-1 in hypoxic retinal Müller cells, and can promote vascular permeability. Our findings suggest that ANGPTL4 may be a potential therapeutic target for ischemic retinopathies.