title: The interaction of heparan sulfate proteoglycans with endothelial transglutaminase-2 limits VEGF165-induced angiogenesis.
abstract: Sprouting angiogenesis is stimulated by vascular endothelial growth factor (VEGF165) that is localized in the extracellular matrix (ECM) and binds to heparan sulfate (HS)-bearing proteins known as heparan sulfate proteoglycans (HSPGs). VEGF165 presentation by HSPGs enhances VEGF receptor-2 (VEGFR2) signaling. We investigated the effect of TG2, which binds to HSPGs, on the interaction between VEGF165 and HS and angiogenesis. Mice with tg2 deficiency showed transiently enhanced retina vessel formation and increased vascularization of VEGF165-containing Matrigel implants. In addition, endothelial cells in which TG2 was knocked down exhibited enhanced VEGF165-induced sprouting and migration, which was associated with increased phosphorylation of VEGFR2 at Tyr(951) and its targets Src and Akt. TG2 knockdown did not affect the phosphorylation of VEGFR2 at Tyr(1175) or cell proliferation in response to VEGF165 and sprouting or signaling in response to VEGF121. Decreased phosphorylation of VEGFR2 at Tyr(951) was due to ECM-localized TG2, which reduced the binding of VEGF165 to endothelial ECM in a manner that required its ability to bind to HS but not its catalytic activity. Surface plasmon resonance assays demonstrated that TG2 impeded the interaction between VEGF165 and HS. These results show that TG2 controls the formation of VEGF165-HSPG complexes and suggest that this regulation could be pharmacologically targeted to modulate developmental and therapeutic angiogenesis.
authors.affiliation: Collège de France, Center for Interdisciplinary Research in Biology, Paris F-75005, France. CNRS, UMR 7241, Paris F-75005, France. INSERM U1050, Paris F-75005, France. Equipe Labellisée Ligue Contre le Cancer. Universite Pierre et Marie Curie (ED 394), Paris F-75005, France.
authors.forename: Nathan
authors.initials: N
authors.lastname: Beckouche
authors.affiliation: Collège de France, Center for Interdisciplinary Research in Biology, Paris F-75005, France. CNRS, UMR 7241, Paris F-75005, France. INSERM U1050, Paris F-75005, France. Equipe Labellisée Ligue Contre le Cancer.
authors.forename: Marine
authors.initials: M
authors.lastname: Bignon
authors.affiliation: Collège de France, Center for Interdisciplinary Research in Biology, Paris F-75005, France. CNRS, UMR 7241, Paris F-75005, France. INSERM U1050, Paris F-75005, France. Equipe Labellisée Ligue Contre le Cancer. Universite Pierre et Marie Curie (ED 394), Paris F-75005, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Lelarge
authors.affiliation: Collège de France, Center for Interdisciplinary Research in Biology, Paris F-75005, France. CNRS, UMR 7241, Paris F-75005, France. INSERM U1050, Paris F-75005, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mathivet
authors.affiliation: Collège de France, Center for Interdisciplinary Research in Biology, Paris F-75005, France. CNRS, UMR 7241, Paris F-75005, France. INSERM U1050, Paris F-75005, France. Equipe Labellisée Ligue Contre le Cancer. Universite Pierre et Marie Curie (ED 394), Paris F-75005, France.
authors.forename: Cathy
authors.initials: C
authors.lastname: Pichol-Thievend
authors.affiliation: Collège de France, Center for Interdisciplinary Research in Biology, Paris F-75005, France. CNRS, UMR 7241, Paris F-75005, France. INSERM U1050, Paris F-75005, France. Equipe Labellisée Ligue Contre le Cancer.
authors.forename: Sarah
authors.initials: S
authors.lastname: Berndt
authors.affiliation: Universite de Rouen Laboratoire Polymères Biopolymeres Surfaces, UMR CNRS 6270, Mont-Saint-Aignan F-76821, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Hardouin
authors.affiliation: Collège de France, Center for Interdisciplinary Research in Biology, Paris F-75005, France. CNRS, UMR 7241, Paris F-75005, France. INSERM U1050, Paris F-75005, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Garand
authors.affiliation: Collège de France, Center for Interdisciplinary Research in Biology, Paris F-75005, France. CNRS, UMR 7241, Paris F-75005, France. INSERM U1050, Paris F-75005, France. Equipe Labellisée Ligue Contre le Cancer.
authors.forename: Corinne
authors.initials: C
authors.lastname: Ardidie-Robouant
authors.affiliation: Collège de France, Center for Interdisciplinary Research in Biology, Paris F-75005, France. CNRS, UMR 7241, Paris F-75005, France. INSERM U1050, Paris F-75005, France. Equipe Labellisée Ligue Contre le Cancer.
authors.forename: Alain
authors.initials: A
authors.lastname: Barret
authors.affiliation: MRC Toxicology Unit, University of Leicester, Leicester LE1 9HN, UK.
authors.forename: Gerry
authors.initials: G
authors.lastname: Melino
authors.affiliation: Université Grenoble Alpes, Institut de Biologie Structurale (IBS), Grenoble F-38000, France. CNRS, IBS, Grenoble F-38000, France. Commissariat à l'Energie Atomique et aux Energies Alternatives, Direction des Sciences du Vivant, IBS, Grenoble F-38000, France.
authors.forename: Hugues
authors.initials: H
authors.lastname: Lortat-Jacob
authors.affiliation: Collège de France, Center for Interdisciplinary Research in Biology, Paris F-75005, France. CNRS, UMR 7241, Paris F-75005, France. INSERM U1050, Paris F-75005, France. Equipe Labellisée Ligue Contre le Cancer.
authors.forename: Laurent
authors.initials: L
authors.lastname: Muller
authors.affiliation: Collège de France, Center for Interdisciplinary Research in Biology, Paris F-75005, France. CNRS, UMR 7241, Paris F-75005, France. INSERM U1050, Paris F-75005, France. Equipe Labellisée Ligue Contre le Cancer. catherine.monnot@college-de-france.fr.
authors.forename: Catherine
authors.initials: C
authors.lastname: Monnot
authors.affiliation: Collège de France, Center for Interdisciplinary Research in Biology, Paris F-75005, France. CNRS, UMR 7241, Paris F-75005, France. INSERM U1050, Paris F-75005, France. Equipe Labellisée Ligue Contre le Cancer. Department of Pathology, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris F-75010, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Germain
mesh_terms: D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020868:Gene Silencing; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D010766:Phosphorylation; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012160:Retina / Q000473:pathology; D012171:Retinal Vessels / Q000473:pathology; D015398:Signal Transduction; D020349:Surface Plasmon Resonance; D011503:Transglutaminases / Q000235:genetics* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D019812:Heparan Sulfate Proteoglycans; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins