title: Lysyl oxidase-like protein-2 regulates sprouting angiogenesis and type IV collagen assembly in the endothelial basement membrane.
abstract: Sprouting angiogenesis is associated with extensive extracellular matrix (ECM) remodeling. The molecular mechanisms involved in building the vascular microenvironment and its impact on capillary formation remain elusive. We therefore performed a proteomic analysis of ECM from endothelial cells maintained in hypoxia, a major stimulator of angiogenesis. Here, we report the characterization of lysyl oxidase-like protein-2 (LOXL2) as a hypoxia-target expressed in neovessels and accumulated in the endothelial ECM. LOXL2 belongs to the lysyl oxidase family of secreted enzymes involved in ECM crosslinking. Knockdown experiments in Tg(fli1:egfp)y1 zebrafish embryos resulted in lack of intersegmental vessel circulation and demonstrated LOXL2 involvement in proper capillary formation. Further investigation in vitro by loss and gain of function experiments confirmed that LOXL2 was required for tubulogenesis in 3D fibrin gels and demonstrated that this enzyme was required for collagen IV assembly in the ECM. In addition, LOXL2 depletion down-regulated cell migration and proliferation. These data suggest a major role for LOXL2 in the organization of endothelial basal lamina and in the downstream mechanotransductive signaling. Altogether, our study provides the first evidence for the role of LOXL2 in regulating angiogenesis through collagen IV scaffolding.
authors.affiliation: College de France, Center for Interdisciplinary Research in Biology, Paris, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Bignon
authors.forename: Cathy
authors.initials: C
authors.lastname: Pichol-Thievend
authors.forename: Julie
authors.initials: J
authors.lastname: Hardouin
authors.forename: Marilyne
authors.initials: M
authors.lastname: Malbouyres
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bréchot
authors.forename: Luiz
authors.initials: L
authors.lastname: Nasciutti
authors.forename: Alain
authors.initials: A
authors.lastname: Barret
authors.forename: Jérémie
authors.initials: J
authors.lastname: Teillon
authors.forename: Emilie
authors.initials: E
authors.lastname: Guillon
authors.forename: Eric
authors.initials: E
authors.lastname: Etienne
authors.forename: Michel
authors.initials: M
authors.lastname: Caron
authors.forename: Raymonde
authors.initials: R
authors.lastname: Joubert-Caron
authors.forename: Catherine
authors.initials: C
authors.lastname: Monnot
authors.forename: Florence
authors.initials: F
authors.lastname: Ruggiero
authors.forename: Laurent
authors.initials: L
authors.lastname: Muller
authors.forename: Stéphane
authors.initials: S
authors.lastname: Germain
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001485:Basement Membrane / Q000378:metabolism*; D015687:Cell Hypoxia; D002460:Cell Line; D002465:Cell Movement; D024141:Collagen Type IV / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D015854:Up-Regulation; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D024141:Collagen Type IV; D029961:Zebrafish Proteins; D000594:Amino Acid Oxidoreductases; C119091:LOXL2 protein, human; C485601:Loxl2 protein, mouse; C568327:loxl2b protein, zebrafish