Neuropilin-1 and neuropilin-2 act as coreceptors, potentiating proangiogenic activity.
Neuropilin-1 and -2 (NRP1 and NRP2) are the transmembrane glycoproteins interacting with 2 types of ligands: class III semaphorins and several members of the VEGF family, the main regulators of blood and lymphatic vessel growth. We show here that both NRP1 and NRP2 can also bind hepatocyte growth factor (HGF). HGF is a pleiotropic cytokine and potent proangiogenic molecule that acts on its target cells by binding to the c-met receptor. We found that the N-terminal domain of HGF is involved in the interaction with neuropilins. We demonstrated that invalidation of NRP1 or NRP2 by RNA interference in human umbilical vein endothelial cells (HUVECs) decreased HGF-induced c-met phosphorylation and VEGF-A(165)- and HGF-mediated intracellular signaling. Accordingly, the disruption of NRP1 or NRP2 binding to VEGF-A(165) or HGF with a blocking antibody, decreased the proliferation and migration of endothelial cells. This effect may be further enhanced if VEGF-A(165) or HGF binding to both NRP1 and NRP2 was disrupted. Using a mouse Matrigel model, we demonstrated that NRP1 is essential for HGF-mediated angiogenesis in vivo. Our results suggest that, in endothelial cells, both NRP1 and NRP2 function as proangiogenic coreceptors, potentiating the activity of at least 2 major proangiogenic cytokines, VEGF-A(165) and HGF.
Institut des Vaisseaux et du Sang, Centre de Recherche Cardiovasculaire Lariboisière Inserm U 689; Université Paris VII; AP-HP Lariboisière, Paris, France.
Eric
E
Sulpice
Jean
J
Plouët
Mathieu
M
Bergé
David
D
Allanic
Gérard
G
Tobelem
Tatyana
T
Merkulova-Rainon
D018929:Cell Culture Techniques; D004261:DNA Replication; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000502:physiology; D006801:Humans; D018919:Neovascularization, Physiologic; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism*; D039943:Neuropilin-2 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014471:Umbilical Veins; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology
D039943:Neuropilin-2; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; D017228:Hepatocyte Growth Factor