Effects of Tetrathiomolybdate in a Mouse Model of Retinal Neovascularization

Abstract

To determine the effects of tetrathiomolybdate (TM), a copper-chelating agent, on retinal angiogenesis and vascular endothelial growth factor (VEGF) in a mouse model of retinal neovascularization. Postnatal day (P)7 C57BL/6N mice were exposed to 75% +/- 2% oxygen for 5 days (P7-P11) and then returned to room air for 5 days (P12-P17) to induce retinal neovascularization. Beginning on P10 or P12, mice received daily intraperitoneal injections of TM or phosphate-buffered saline (PBS; control) through P17. Retinal neovascularization was examined by fluorescein dextran angiography after 5 days in room air and was quantitated histologically by counting the neovascular endothelial cell nuclei anterior to the inner limiting membrane. TM's effects on VEGF expression were measured by ELISA. TM-treated and control animals demonstrated comparable regions of retinal nonperfusion. Retinas from control mice at P17 contained neovascular tufts at the junction between perfused and nonperfused retina. The tufts contained numerous neovascular nuclei. Retinas from mice treated with TM beginning on P10 (2 days before returning to room air), but not P12, demonstrated a 41% reduction in neovascular cell nuclei compared with control mice (P <0.01). The P10-treated mice also demonstrated a 24% reduction of VEGF compared with control animals (P=0.01). TM significantly inhibits retinal neovascularization and VEGF production in a mouse model of retinal neovascularization.