title: The endothelial adaptor molecule TSAd is required for VEGF-induced angiogenic sprouting through junctional c-Src activation.
abstract: Activation of vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) by VEGF binding is critical for vascular morphogenesis. In addition, VEGF disrupts the endothelial barrier by triggering the phosphorylation and turnover of the junctional molecule VE-cadherin, a process mediated by the VEGFR2 downstream effectors T cell-specific adaptor (TSAd) and the tyrosine kinase c-Src. We investigated whether the VEGFR2-TSAd-c-Src pathway was required for angiogenic sprouting. Indeed, Tsad-deficient embryoid bodies failed to sprout in response to VEGF. Tsad-deficient mice displayed impaired angiogenesis specifically during tracheal vessel development, but not during retinal vasculogenesis, and in VEGF-loaded Matrigel plugs, but not in those loaded with FGF. The SH2 and proline-rich domains of TSAd bridged VEGFR2 and c-Src, and this bridging was critical for the localization of activated c-Src to endothelial junctions and elongation of the growing sprout, but not for selection of the tip cell. These results revealed that vascular sprouting and permeability are both controlled through the VEGFR2-TSAd-c-Src signaling pathway in a subset of tissues, which may be useful in developing strategies to control tissue-specific pathological angiogenesis.
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjöldsv 20, Uppsala 75185, Sweden. emma.gordon@igp.uu.se lena.welsh@igp.uu.se.
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Gordon
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjöldsv 20, Uppsala 75185, Sweden.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Fukuhara
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjöldsv 20, Uppsala 75185, Sweden.
authors.forename: Simone
authors.initials: S
authors.lastname: Weström
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjöldsv 20, Uppsala 75185, Sweden.
authors.forename: Narendra
authors.initials: N
authors.lastname: Padhan
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjöldsv 20, Uppsala 75185, Sweden.
authors.forename: Elisabet O
authors.initials: EO
authors.lastname: Sjöström
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjöldsv 20, Uppsala 75185, Sweden.
authors.forename: Laurens
authors.initials: L
authors.lastname: van Meeteren
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjöldsv 20, Uppsala 75185, Sweden.
authors.forename: Liqun
authors.initials: L
authors.lastname: He
authors.affiliation: FIRC Institute of Molecular Oncology Foundation, IFOM, Milan 20139, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Orsenigo
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjöldsv 20, Uppsala 75185, Sweden. FIRC Institute of Molecular Oncology Foundation, IFOM, Milan 20139, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Dejana
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjöldsv 20, Uppsala 75185, Sweden. Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Katie
authors.initials: K
authors.lastname: Bentley
authors.affiliation: Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo 0317, Norway.
authors.forename: Anne
authors.initials: A
authors.lastname: Spurkland
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjöldsv 20, Uppsala 75185, Sweden. emma.gordon@igp.uu.se lena.welsh@igp.uu.se.
authors.forename: Lena
authors.initials: L
authors.lastname: Claesson-Welsh
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C402726:Sh2d2a protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases