title: Involvement of VEGFR-2 (kdr/flk-1) but not VEGFR-1 (flt-1) in VEGF-A and VEGF-C-induced tube formation by human microvascular endothelial cells in fibrin matrices in vitro.
abstract: Different forms of vascular endothelial growth factor (VEGF) and their cellular receptors (VEGFR) are associated with angiogenesis, as demonstrated by the lethality of VEGF-A, VEGFR-1 or VEGFR-2 knockout mice. Here we have used an in vitro angiogenesis model, consisting of human microvascular endothelial cells (hMVEC) cultured on three-dimensional (3D) fibrin matrices to investigate the roles of VEGFR-1 and VEGFR-2 in the process of VEGF-A and VEGF-C-induced tube formation. Soluble VEGFR-1 completely inhibited the tube formation induced by the combination of VEGF-A and TNF alpha (VEGF-A/TNF alpha). This inhibition was not observed when tube formation was induced by VEGF-C/TNF alpha or bFGF/TNF alpha. Blocking monoclonal antibodies specific for VEGFR-2, but not antibodies specifically blocking VEGFR-1, were able to inhibit the VEGF-A/TNF alpha-induced as well as the VEGF-C/TNF alpha-induced tube formation in vitro. P1GF-2, which interacts only with VEGFR-1, neither induced tube formation in combination with TNF alpha, nor inhibited or stimulated by itself the VEGF-A/TNF alpha-induced tube formation in vitro. These data indicate that VEGF-A or VEGF-C activation of the VEGFR-2, and not of VEGFR-1, is involved in the formation of capillary-like tubular structures of hMVEC in 3D fibrin matrices used as a model of repair-associated or pathological angiogenesis in vitro.
authors.affiliation: Gaubius Laboratory TNO-PG, Zernikedreef 9, 2333 CK Leiden, The Netherlands. p.koolwijk@pg.tno.nl
authors.forename: P
authors.initials: P
authors.lastname: Koolwijk
authors.forename: E
authors.initials: E
authors.lastname: Peters
authors.forename: B
authors.initials: B
authors.lastname: van der Vecht
authors.forename: C
authors.initials: C
authors.lastname: Hornig
authors.forename: H A
authors.initials: HA
authors.lastname: Weich
authors.forename: K
authors.initials: K
authors.lastname: Alitalo
authors.forename: D J
authors.initials: DJ
authors.lastname: Hicklin
authors.forename: Y
authors.initials: Y
authors.lastname: Wu
authors.forename: L
authors.initials: L
authors.lastname: Witte
authors.forename: V W
authors.initials: VW
authors.lastname: van Hinsbergh
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000254:growth & development* / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008955:Models, Cardiovascular; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D040262:Receptors, Vascular Endothelial Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D040281:Vascular Endothelial Growth Factor Receptor-1
chemical_list: D000911:Antibodies, Monoclonal; D016228:Endothelial Growth Factors; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1