An antisense oligodeoxyribonucleotide down-regulating uPAR expression inhibits retinal neoangiogenesis both in vitro and in in vivo

The main pathogenetic event of severe retinal diseases known as proliferative retinopathies is neoangiogenesis. This hypoxia-induced process, by which new blood vessels are formed by the sprouting of endothelial cells from preexisting vessels, results from upregulation of specific proteases, included urokinase (uPA) and its receptor (uPAR), which induce matrix remodeling and cell migration. On the basis of our previous results and evidences reported in the literature, we have hypothesized that uPAR knocking down by antisense oligonucleotides (ODNs) could reduce retinal vessel production. Both human retinal endothelial cells (hREC) and a mouse model of neoangiogenesis-related retinopathy (premature retinopathy) have been used. uPAR knocking down was obtained by a chemically stabilized anti-uPAR aODN added to the culture medium or injected intraperitoneally (IP) for the in vitro or in vivo experiments, respectively. The anti-uPAR aODN markedly inhibited uPAR expression in cultured hREC cells and lowered capillary morphogenesis, proliferation, migration and invasion of Matrigel. When applied IP to the retinopathy mouse model, the aODN reached the retina, where it lowered uPAR expression, thereby markedly increasing the retina avascular areas and reducing the retinopathy score. Research supported by ECR Firenze, FCR Lucca and ASI (Agenzia Spaziale Italiana).