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 (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 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 (VEGF165). OTR4120 showed high affinity binding to VEGF165 (Kd = 2.2 nm), as compared with heparin (Kd = 15 nm), and potentiated the affinity of VEGF165 for VEGF receptor-1 and -2 and for neuropilin-1. In vitro, OTR4120 potentiated VEGF165-induced proliferation and migration of human umbilical vein endothelial cells. In the in vivo Matrigel plug angiogenesis assay, OTR4120 in a concentration as low as 3 ng/ml caused a 6-fold increase in VEGF165-induced angiogenesis. Immunohistochemical staining showed a larger number of well differentiated VEGFR-2-expressing-cells in Matrigel sections of OTR4120-treated plug than in control sections. These findings indicate that OTR4120 enhances the VEGF165-induced angiogenesis and therefore may hold promise for treating disorders characterized by deficient angiogenesis.
Rouet
Vincent
V
Laboratoire de Recherche sur la Croissance Cellulaire, la Réparation et la Régénération Tissulaires UMR CNRS 7149, Université Paris XII-Val de Marne, Avenue du Général de Gaulle, 94010 Créteil CEDEX, France.
Hamma-Kourbali
Yamina
Y
Petit
Emmanuel
E
Panagopoulou
Panagiota
P
Katsoris
Panagiotis
P
Barritault
Denis
D
Caruelle
Jean-Pierre
JP
Courty
José
J
D000818:Animals; D002417:Cattle; D002448:Cell Adhesion; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D002642:Chick Embryo; D003094:Collagen / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology; D006025:Glycosaminoglycans / Q000737:chemistry*; D006801:Humans; D007150:Immunohistochemistry; D007700:Kinetics; D007797:Laminin / Q000494:pharmacology; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D011485:Protein Binding; D011509:Proteoglycans / Q000494:pharmacology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012710:Serum Albumin, Bovine / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry / Q000378:metabolism*
D004338:Drug Combinations; D006025:Glycosaminoglycans; D007797:Laminin; D011509:Proteoglycans; D011993:Recombinant Fusion Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D012710:Serum Albumin, Bovine; D003094:Collagen; D040262:Receptors, Vascular Endothelial Growth Factor