The uPA/uPAR System in Retinal Neovascularization: A Target for Anti-angiogenic Therapy

Abstract

Abstract: : Purpose: To determine the role of urokinase (uPA) and its receptor uPAR in the promotion and regulation of angiogenesis in the retina, and whether inhibition of this proteolytic system can suppress the extent of retinal neovascularization (NV) in a well-established animal model. Methods: Retinal NV was induced in mice by exposure to 75% oxygen on postnatal days 7-12 followed by exposure to room air on days 12-17. The expression of uPA and uPAR in the retina of experimental animals was analyzed by zymography and RT-PCR and compared to room air controls. The effects of inhibiting the uPA/uPAR system on the development of retinal NV was studied in the animal model. The uPA/uPAR systme was inhibited by the intraperitoneal injection of oxygen-treated mice with the peptide Å6 (Ångstrom Pharmaceuticals). Injections were given at 100 mg/kg bid on days 12-16. The angiogenic response in these mice was further compared to that observed in mice that lacked uPAR expression. Results: The expression of uPA and uPAR are significantly increased in mice with developing retinal NV. Histological analysis of mice treated with Å6 showed significant inhibition of NV (up to 63%) with no detectable side-effects. This degree of inhibition was comparable to that seen in the uPAR- deficient mice which showed 77% less retinal NV as compared to the normal Bl6 mice. Conclusion: The activity of the uPA / uPAR system is upregulated during the development of retinal NV in mice. Significant inhibition of NV was seen when cell surface - associated uPA/uPAR activity was prevented with Å6, a treatment with no detectable side-effects.

Keywords: 566 retinal neovascularization • 614 vascular cells • 316 animal model