title: Laminin-binding integrins induce Dll4 expression and Notch signaling in endothelial cells.
abstract: BACKGROUND
  Integrins play a crucial role in controlling endothelial cell proliferation and migration during angiogenesis. The Delta-like 4 (Dll4)/Notch pathway establishes an adequate ratio between stalk and tip cell populations by restricting tip cell formation through "lateral inhibition" in response to a vascular endothelial growth factor gradient. Because angiogenesis requires a tight coordination of these cellular processes, we hypothesized that adhesion, vascular endothelial growth factor, and Notch signaling pathways are interconnected.
  
  
  OBJECTIVE
  This study was aimed at characterizing the cross-talk between integrin and Notch signaling in endothelial cells.
  
  
  RESULTS
  Adhesion of primary human endothelial cells to laminin-111 triggers Dll4 expression, leading to subsequent Notch pathway activation. SiRNA-mediated knockdown of α2β1 and α6β1 integrins abolishes Dll4 induction, which discloses a selective integrin signaling acting upstream of Notch pathway. The increase in Foxc2 transcription, triggered by α2β1 binding to laminin, is required but not sufficient per se for Dll4 expression. Furthermore, vascular endothelial growth factor stimulates laminin γ1 deposition, which leads to integrin signaling and Dll4 induction. Interestingly, loss of integrins α2 or α6 mimics the effects of Dll4 silencing and induces excessive network branching in an in vitro sprouting angiogenesis assay on three-dimensional matrigel.
  
  
  CONCLUSIONS
  We show that, in endothelial cells, ligation of α2β1 and α6β1 integrins induces the Notch pathway, and we disclose a novel role of basement membrane proteins in the processes controlling tip vs stalk cell selection.
authors.affiliation: INSERM, U634, Nice F-06107, France.
authors.forename: Soline
authors.initials: S
authors.lastname: Estrach
authors.forename: Laurence
authors.initials: L
authors.lastname: Cailleteau
authors.forename: Claudio Areias
authors.initials: CA
authors.lastname: Franco
authors.forename: Holger
authors.initials: H
authors.lastname: Gerhardt
authors.forename: Caroline
authors.initials: C
authors.lastname: Stefani
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Lemichez
authors.forename: Laurent
authors.initials: L
authors.lastname: Gagnoux-Palacios
authors.forename: Guerrino
authors.initials: G
authors.lastname: Meneguzzi
authors.forename: Amel
authors.initials: A
authors.lastname: Mettouchi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001485:Basement Membrane; D002135:Calcium-Binding Proteins; D002448:Cell Adhesion; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D038982:Integrin alpha2beta1 / Q000378:metabolism*; D039121:Integrin alpha6beta1 / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D007797:Laminin / Q000378:metabolism; D008565:Membrane Proteins / Q000502:physiology; D018919:Neovascularization, Physiologic; D020239:Receptor Cross-Talk; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D038982:Integrin alpha2beta1; D039121:Integrin alpha6beta1; D016023:Integrins; D036341:Intercellular Signaling Peptides and Proteins; D007797:Laminin; D008565:Membrane Proteins; D051880:Receptors, Notch