Inhibition of Basic Fibroblast Growth Factor Induced Rat Corneal Angiogenesis by a Urokinase Plasminogen Activator Receptor Antagonist

ABSTRACT

During angiogenesis, binding of urokinase plasminogen activator(uPA) and its receptor(uPAR) has been implicated as an important component of the angiogenesis pathway. We have produced a high-affinity competitive antagonist for the uPA receptor consisting of a fusion protein linking the endothelial growth factor(EGF)-like domain of uPA(residues 1-48) to the Fc domain of IgG. To determine whether this recombinant murine uPA1-48-IgG fusion protein could interfere with angiogenesis, we studied the effect of this compound on rat corneal angiogenesisinduced by basic fibroblast growth factor(bFGF). A hydrogel disk containing 250ng of bFGF and 4.2ug of uPA1-48-IgG fusiong protein in seven eyes, 250ug of bFGF and 4.2ug of phosphate-buffered saline(PBS) in another sseven eyes were implanted intrastromally 1.5mm from the superior limbus. At five days post-implantation of bFGF disk, the eyes treated with uPA1-48IgG fusion protein had reduced angiogenesis (mean score=3.1) compared with the PBS-treated controls(mean score=6.1)(P<0.05, Wilcoxon rank sum test). In a rat corneal pocket assay, murine uPA1-48-IgG fusion protein appears to inhibit bFGF-induced angiogenesis. Compounds that block uPAR binding of uPA may have therapeutic potential as anti-angiogenic agents.