Inducing a Visceral Organ to Protect a Peripheral Capillary Bed Stabilizing Hepatic HIF-1α Prevents Oxygen-Induced Retinopathy

Activation of hypoxia-inducible factor (HIF) can prevent oxygen-induced retinopathy in rodents. Here we demonstrate that dimethyloxaloylglycine (DMOG)-induced retinovascular protection is dependent on hepatic HIF-1 because mice deficient in liver-specific HIF-1 alpha experience hyperoxia-induced damage even with DMOG treatment, whereas DMOG-treated wild-type mice have 50% less avascular retina (P < 0.0001). Hepatic HIF stabilization protects retinal function because DMOG normalizes the b-wave on electroretinography in wild-type mice. The localization of DMOG action to the Liver is further supported by evidence that i) mRNA and protein erythropoietin levels within Liver and serum increased in DMOG-treated wild-type animals but are reduced by 60 /0 in Liver-specific HIF-1 alpha knockout mice treated with DMOG, ii) triple-positive (Sca1/cKit/VEGFR2), bone-marrow derived endothelial precursor cells increased twofold in DMOG-treated wild-type mice (P < 0.001) but are unchanged in hepatic HIF-1 alpha knockout mice in response to DMOG, and iii) hepatic luminescence in the luciferase oxygen-dependent degradation domain mouse was induced by subcutaneous and intraperitoneal DMOG. These findings uncover a novel endocrine mechanism for retinovascular protection. Activating HIF in visceral organs such as the Liver may be a simple strategy to protect capillary beds in the retina and in other peripheral tissues.