Vascular Endothelial Growth Factor B (VEGF-B) Binds to VEGF Receptor-1 and Regulates Plasminogen Activator Activity in Endothelial Cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 95; no. 20; pp. 11709 - 11714
• Main Authors: Olofsson, Birgitta, Korpelainen, Eija, Pepper, Michael S., Mandriota, Stefano J., Aase, Karin, Kumar, Vijay, Gunji, Yuji, Jeltsch, Michael M., Shibuya, Masabumi, Alitalo, Kari, Eriksson, Ulf
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 29.09.1998; National Acad Sciences; National Academy of Sciences
• Subjects: 3T3 Cells; Animals; Antibodies; B lymphocytes; Baculoviridae - genetics; Base Sequence; Binding Sites - genetics; Biological Sciences; Blood vessels; Cattle; Cell growth; Cells; Cells, Cultured; Cellular biology; Cysteine - genetics; Dimers; DNA Primers - genetics; Endothelial cells; Endothelial Growth Factors - genetics; Endothelial Growth Factors - metabolism; Endothelium, Vascular - cytology; Endothelium, Vascular - metabolism; Medicin och hälsovetenskap; Mice; Mutagenesis, Site-Directed; NIH 3T3 cells; Plasminogen Activator Inhibitor 1 - biosynthesis; Plasminogen activators; Plasminogen Activators - metabolism; Protein Processing, Post-Translational; Proteins; Proto-Oncogene Proteins - metabolism; Receptor Protein-Tyrosine Kinases - metabolism; Receptors; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Spodoptera; Transfection; Urokinase-Type Plasminogen Activator - biosynthesis; Vascular Endothelial Growth Factor B; Vascular Endothelial Growth Factor Receptor-1
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.95.20.11709

The vascular endothelial growth factor (VEGF) family has recently expanded by the identification and cloning of three additional members, namely VEGF-B, VEGF-C, and VEGF-D. In this study we demonstrate that VEGF-B binds selectively to VEGF receptor-1/Flt-1. This binding can be blocked by excess VEGF, indicating that the interaction sites on the receptor are at least partially overlapping. Mutating the putative VEGF receptor-1/Flt-1 binding determinants Asp63, Asp64, and Glu67 to alanine residues in VEGF-B reduced the affinity to VEGF receptor-1 but did not abolish binding. Mutational analysis of conserved cysteines contributing to VEGF-B dimer formation suggest a structural conservation with VEGF and platelet-derived growth factor. Proteolytic processing of the 60-kDa VEGF-B186 dimer results in a 34-kDa dimer containing the receptor-binding epitopes. The binding of VEGF-B to its receptor on endothelial cells leads to increased expression and activity of urokinase type plasminogen activator and plasminogen activator inhibitor 1, suggesting a role for VEGF-B in the regulation of extracellular matrix degradation, cell adhesion, and migration.