Differential binding of vascular endothelial growth factor B splice and proteolytic isoforms to Neuropilin-1

Abstract

Vascular endothelial growth factor B (VEGF-B) is expressed in various tissues, especially strongly in the heart, and binds selectively to one of the VEGF receptors, VEGFR-1. The two splice isoforms, VEGF-B167 and VEGF- B186, have identical NH2-terminal cystine knot growth factor domains but differ in their COOH-terminal domains which give these forms their distinct biochemical properties. In this study, we show that both splice isoforms of VEGF-B bind specifically to Neuropilin-1 (NRP1), a receptor for collapsins/semaphorins and for the VEGF165 isoform. The NRP1 binding of VEGF-B could be competed by an excess of VEGF165. The binding of VEGF- B167 was mediated by the heparin binding domain, whereas the binding of VEGF-B186 to NRP1 was regulated by exposure of a short COOH-terminal proline-rich peptide upon its proteolytic processing. In immunohistochemistry, NRP1 distribution was found to be overlapping or adjacent to known sites of VEGF-B expression in several tissues, in particular in the developing heart, suggesting the involvement of VEGF-B in NRPl-mediated signaling.