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J. Cell Biol., Volume 146, Number 1, July 12, 1999 233-242
Copyright © 1999 by The Rockefeller University Press.

Neuropilin-1 Mediates Collapsin-1/Semaphorin III Inhibition of Endothelial Cell Motility: Functional Competition of Collapsin-1 and Vascular Endothelial Growth Factor-165

Hua-Quan Miaoa, Shay Sokera,c, Leonard Feinerd, José Luis Alonsoa, Jonathan A. Raperd, and Michael Klagsbruna,b
a Department of Surgical Research, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115
b Department of Pathology, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115
c Department of Urology, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115
d Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Correspondence to: Michael Klagsbrun, Department of Surgical Research, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115., klagsbrun{at}a1.tch.harvard.edu (E-mail), (617) 355-7503 (phone), (617) 355-7291 (fax)

Neuropilin-1 (NRP1) is a receptor for two unrelated ligands with disparate activities, vascular endothelial growth factor-165 (VEGF165), an angiogenesis factor, and semaphorin/collapsins, mediators of neuronal guidance. To determine whether semaphorin/collapsins could interact with NRP1 in nonneuronal cells, the effects of recombinant collapsin-1 on endothelial cells (EC) were examined. Collapsin-1 inhibited the motility of porcine aortic EC (PAEC) expressing NRP1 alone; coexpressing KDR and NRP1 (PAEC/KDR/NRP1), but not parental PAEC; or PAEC expressing KDR alone. The motility of PAEC expressing NRP1 was inhibited by 65–75% and this inhibition was abrogated by anti-NRP1 antibody. In contrast, VEGF165 stimulated the motility of PAEC/KDR/NRP1. When VEGF165 and collapsin-1 were added simultaneously to PAEC/KDR/NRP1, dorsal root ganglia (DRG), and COS-7/NRP1 cells, they competed with each other in EC motility, DRG collapse, and NRP1-binding assays, respectively, suggesting that the two ligands have overlapping NRP1 binding sites. Collapsin-1 rapidly disrupted the formation of lamellipodia and induced depolymerization of F-actin in an NRP1-dependent manner. In an in vitro angiogenesis assay, collapsin-1 inhibited the capillary sprouting of EC from rat aortic ring segments. These results suggest that collapsin-1 can inhibit EC motility as well as axon motility, that these inhibitory effects on motility are mediated by NRP1, and that VEGF165 and collapsin-1 compete for NRP1-binding sites.

Key Words: angiogenesis, chemotaxis, KDR, neuronal guidance, growth cones


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