Relative effects of VEGF-A and VEGF-C on endothelial cell proliferation, migration and PAF synthesis: Role of neuropilin-1.
Vascular endothelial growth factor (VEGF-A) is an inducer of endothelial cell (EC) proliferation, migration, and synthesis of inflammatory agents such as platelet-activating factor (PAF). Recently, neuropilin-1 (NRP-1) has been described as a coreceptor of KDR which potentiates VEGF-A activity. However, the role of NRP-1 in numerous VEGF-A activities remains unclear. To assess the contribution of NRP-1 to VEGF-A mediated EC proliferation, migration, and PAF synthesis, we used porcine aortic EC (PAEC) recombinantly expressing Flt-1, NRP-1, KDR or KDR and NRP-1. Cells were stimulated with VEGF-A, which binds to Flt-1, KDR and NRP-1, and VEGF-C, which binds to KDR only. VEGF-A was 12.4-fold more potent than VEGF-C in inducing KDR phosphorylation in PAEC-KDR. VEGF-A and VEGF-C showed similar potency to mediate PAEC-KDR proliferation, migration, and PAF synthesis. On PAEC-KDR/NRP-1, VEGF-A was 28.6-fold more potent than VEGF-C in inducing KDR phosphorylation and PAEC-KDR/NRP-1 proliferation (1.3-fold), migration (1.7-fold), and PAF synthesis (4.6-fold). These results suggest that cooperative binding of VEGF-A to KDR and NRP-1 enhances KDR phosphorylation and its biological activities. Similar results were obtained with bovine aortic EC that endogenously express both KDR and NRP-1 receptors. In contrast, stimulation of PAEC-Flt-1 and PAEC-NRP-1 with VEGF-A or VEGF-C did not induce proliferation, migration, or PAF synthesis. In conclusion, the presence of NRP-1 on EC preferentially increases KDR activation by VEGF-A as well as KDR-mediated biological activities, and may elicit novel intracellular events. On the other hand, VEGF-A and VEGF-C have equipotent biological activities on EC in absence of NRP-1.
Bernatchez
Pascal N
PN
Research Center, Montreal Heart Institute, and Department of Pharmacology, University of Montreal, Montreal, Quebec, Canada, H1T 1C8.
Rollin
Simon
S
Soker
Shay
S
Sirois
Martin G
MG
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D039942:Neuropilin-1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D010972:Platelet Activating Factor / Q000096:biosynthesis* / Q000187:drug effects; D011485:Protein Binding / Q000502:physiology; D013552:Swine; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C
D016228:Endothelial Growth Factors; D016326:Extracellular Matrix Proteins; D010972:Platelet Activating Factor; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D039942:Neuropilin-1