Anti-angiogenic effectiveness of the urokinase receptor-derived peptide UPARANT in a model of oxygen induced retinopathy

Purpose. Pharmacologic control of neovascularization is a promising approach for the treatment of retinal angiogenesis. UPARANT, an inhibitor of the urokinase-type plasminogen activator receptor (uPAR), inhibits vascular endothelial growth factor (VEGF)-driven angiogenesis in vitro and in vivo. This study investigates for the first time the effectiveness of UPARANT in counteracting pathological neovascularization in the retina. Methods. Murine retinal fragments and a mouse model of oxygen induced retinopathy (OIR) were used. In OIR mice, UPARANT-treated retinas were analyzed for avascular area and neovascular tuft formation. Levels of transcription and proangiogenic factors were determined. UPARANT effects on blood retinal barrier (BRB), visual function, retinal cytoarchitecture and inflammatory markers were also assessed. Human umbilical vein endothelial cells (HUVECs) and chick embryo chorioallantoic membrane (CAM) in which angiogenesis was induced by the vitreous fluid from patients with proliferative diabetic retinopathy (PDR) were also used. Results. UPARANT reduced VEGF-induced angiogenesis in retinal fragments. In OIR mice, UPARANT decreased neovascular response, VEGF and VEGF receptor 2 activity. Transcription factors regulating VEGF expression were also reduced. UPARANT restored BRB integrity, recovered visual loss, reduced levels of inflammatory markers. Restored ERG does not involve any rescue in the retinal cytoarchitecture. Finally, UPARANT blocked PDR vitreous fluid-induced angiogenesis in HUVEC and CAM assays. Conclusions. The finding that UPARANT is effective against neovascularization may help to establish uPAR as a target in the treatment of proliferative retinopathies. The potential application of UPARANT in retinal diseases is further supported by UPARANT capacity to counteract the angiogenic activity of PDR vitreous fluid.