A synthetic glycosaminoglycan mimetic binds vascular endothelial growth factor and modulates angiogenesis

In a previous study, we showed that in situ injection of glycosaminoglycan mimetics called RGTAs (R) (ReGeneraTing Agents) enhanced neovascularization after skeletal muscular ischemia ( Desgranges, P., Barbaud, C., Caruelle, J. P., Barritault, D., and Gautron, J. ( 1999) FASEB J. 13, 761 - 766). In the present study, we showed that the RGTA (R) OTR4120 modulated angiogenesis in the chicken embryo chorioallantoic membrane assay, in a dose-dependent manner. We therefore investigated the effect of OTR4120 on one of the most specific angiogenesis-regulating heparin-binding growth factors, vascular endothelial growth factor 165 ( VEGF(165)). OTR4120 showed high affinity binding to VEGF(165) (K-d = 2.2 nM), as compared with heparin (K-d = 15 nM), and potentiated the affinity of VEGF(165) for VEGF receptor-1 and -2 and for neuropilin-1. In vitro, OTR4120 potentiated VEGF(165)-induced proliferation and migration of human umbilical vein endothelial cells. In the in vivo Matrigel (TM) plug angiogenesis assay, OTR4120 in a concentration as low as 3 ng/ml caused a 6-fold increase in VEGF(165)-induced angiogenesis. Immunohistochemical staining showed a larger number of well differentiated VEGFR-2-expressing-cells in Matrigel (TM) sections of OTR4120-treated plug than in control sections. These findings indicate that OTR4120 enhances the VEGF(165)-induced angiogenesis and therefore may hold promise for treating disorders characterized by deficient angiogenesis.