To determine the role played by the urokinase plasminogen activator(uPA) and urokinase plasminogen activator receptor (uPAR) system in choroidalneovascularization (CNV) and whether inhibition of this system can suppressthe extent of CNV in an animal model.
Choroidal neovascularization was induced in mice by laser photocoagulationusing the slitlamp delivery system. Reverse transcriptase–polymerasechain reaction and immunocytochemical analysis were performed on the retinachoroids of these animals to examine the expression of uPAR. For 2 weeks followinglaser treatment, animals were injected intraperitoneally with a novel peptideinhibitor of the uPA-uPAR system (100 mg/kg twice a day every day, every otherday, and once a week). Control laser-treated animals receive an intraperitonealinjection of phosphate-buffered saline every day. Following treatment, animalswere perfused with fluorescein-labeled dextran, eyes were removed, and theareas of new vessels were examined in the retina-choroid whole mounts by fluorescencemicroscopy and quantitated using image analysis software.
In this study, uPAR was found to be up-regulated in the choroidal tissuesof mice with laser-induced CNV. The uPAR was localized to the endothelialcells of the fibrovascular tissue within the CNV complex. Systemic administrationof the peptide inhibitor of the uPA-uPAR system resulted in a significantreduction of CNV (up to 94%). The response was found to be frequency-of-dosedependent. No toxic effects or tissue destruction was noted following thepeptide treatment.
Our results strongly suggest that up-regulation of the uPA-uPAR systemis an important step during CNV, and significant inhibition of CNV was seenwhen cell surface–associated uPA-uPAR activity was prevented with thepeptide inhibitor.
Inhibition of the protease system (uPA-uPAR) may prove to be a potentialnovel antiangiogenic therapy for CNV as seen in age-related macular degeneration.