Neuropilin-1 is a placenta growth factor-2 receptor

Placenta growth factor (PIGF) belongs to the family of vascular endothelial growth factors (VEGFs). It binds to the flt-1 VEGF receptor but not to the KDR/flk-1 receptor which is thought to mediate most of the angiogenic and proliferative effects of VEGF, Three PIGF isoforms are produced by alternative splicing. PlGF-1 and PlGF-3 differ from PlGF-2 since they lack the exon 6 encoded peptide which bestows upon PlGF-2 its heparin binding properties. Cross-linking experiments revealed that I-125-PlGF-2 binds to two endothelial cell surface receptors in a heparin dependent fashion. The binding of I-125-PlGF-2 to these receptors was inhibited by an excess of PlGF-2 and by the 165-amino acid form of VEGF (VEGF(165)), but not at all by VEGF(165) and very marginally if at all by PlGF-1, The apparent molecular weight and the binding characteristics of these receptors correspond to those of the recently identified VEGF(165) specific receptor neuropilin-1, and we therefore conclude that neuropilin-1 is a receptor for PlGF-2. The binding of I-125-PlGF-2 as well as the binding of I-125-VEGF(165) to these receptors was inhibited by a synthetic peptide derived from exon 6 of PlGF. Furthermore, the binding of I-125-PIGF-2, but not that of I-125-VEGF(165), was also inhibited by a synthetic peptide derived from exon 7 of PlGF. These observations indicate that the peptides encoded by these exons probably participate in the formation of the domain which mediates the binding of PlGF-2 to these receptors, We have also determined, using chemically modified heparin species, that the presence of sulfate moieties on the glucosamine-O-6 and on the iduronic acid-O-2 groups of heparin was required for the potentiation of I-125-PlGF-2 binding to these receptors. To determine if PlGF-2 is able to induce biological responses that are not induced by PlGF-1, we compared the effects of PlGF-1 and PlGF-2 on the migration and proliferation of endothelial cells. Both PlGF forms induced migration of endothelial cells. However, there was no quantitative difference between the response to PIGF-2 and the response to PIGF-1. Furthermore, neither PIGF-1 nor PlGF-2 had any effect upon the proliferation of the endothelial cells.