title: Vascular endothelial growth factor (VEGF) receptor-2 signaling mediates VEGF-C(deltaNdeltaC)- and VEGF-A-induced angiogenesis in vitro.
abstract: Angiogenesis and lymphangiogenesis are regulated by members of the vascular endothelial growth factor (VEGF) family of cytokines, which mediate their effects via tyrosine kinase VEGF receptors -1, -2, and -3. We have used wild-type and mutant forms of VEGFs -A, -B, and -C, a pan-VEGFR tyrosine kinase inhibitor (SU5416) as well as neutralizing anti-VEGFR-2 antibodies, to determine which VEGF receptor(s) are required for bovine endothelial cell invasion and tube formation in vitro. This was compared to the ability of these cytokines to induce expression of members of the plasminogen activator (PA)-plasmin system. We found that cytokines which bind VEGFR-2 (human VEGF-A, human VFM23A, human VEGF-C(deltaNdeltaC), and rat VEGF-C(152)) induced invasion, tube formation, urokinase-type-PA, tissue-type-PA, and PA inhibitor-1, invasion and tube formation as well as signaling via the MAP kinase pathway were efficiently blocked by SU5416 and anti-VEGFR-2 antibodies. In contrast, cytokines and mutants which exclusively bind VEGFR-1 (human VFM17 and human VEGF-B) had no effect on invasion and tube formation or on the regulation of gene expression. We were unable to identify cytokines which selectively stimulate bovine VEGFR-3 in our system. Taken together, these findings point to the central role of VEGFR-2 in the angiogenic signaling pathways induced by VEGF-C(deltaNdeltaC) and VEGF-A.
authors.affiliation: Department of Cell Biology and Morphology, University Medical Center, Geneva, Switzerland.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Tille
authors.forename: Xueyan
authors.initials: X
authors.lastname: Wang
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Lipson
authors.forename: Gerald
authors.initials: G
authors.lastname: McMahon
authors.forename: Napoleone
authors.initials: N
authors.lastname: Ferrara
authors.forename: Zhenping
authors.initials: Z
authors.lastname: Zhu
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hicklin
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Sleeman
authors.forename: Ulf
authors.initials: U
authors.lastname: Eriksson
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Michael S
authors.initials: MS
authors.lastname: Pepper
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002417:Cattle; D002465:Cell Movement; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000235:genetics / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005341:Fibrinolysin / Q000096:biosynthesis; D007211:Indoles / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D018919:Neovascularization, Physiologic; D010960:Plasminogen Activators / Q000096:biosynthesis; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*
chemical_list: D000906:Antibodies; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D007211:Indoles; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; C116890:Semaxinib; D040301:Vascular Endothelial Growth Factor Receptor-2; D020928:Mitogen-Activated Protein Kinases; D010960:Plasminogen Activators; D005341:Fibrinolysin