title: Angiopoietin 2 regulates the transformation and integrity of lymphatic endothelial cell junctions.
abstract: Primitive lymphatic vessels are remodeled into functionally specialized initial and collecting lymphatics during development. Lymphatic endothelial cell (LEC) junctions in initial lymphatics transform from a zipper-like to a button-like pattern during collecting vessel development, but what regulates this process is largely unknown. Angiopoietin 2 (Ang2) deficiency leads to abnormal lymphatic vessels. Here we found that an ANG2-blocking antibody inhibited embryonic lymphangiogenesis, whereas endothelium-specific ANG2 overexpression induced lymphatic hyperplasia. ANG2 inhibition blocked VE-cadherin phosphorylation at tyrosine residue 685 and the concomitant formation of button-like junctions in initial lymphatics. The defective junctions were associated with impaired lymph uptake. In collecting lymphatics, adherens junctions were disrupted, and the vessels leaked upon ANG2 blockade or gene deletion. ANG2 inhibition also suppressed the onset of lymphatic valve formation and subsequent valve maturation. These data identify ANG2 as the first essential regulator of the functionally important interendothelial cell-cell junctions that form during lymphatic development.
authors.affiliation: Wihuri Research Institute, Translational Cancer Biology Program, University of Helsinki, Helsinki 00014, Finland;
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Wihuri Research Institute, Translational Cancer Biology Program, University of Helsinki, Helsinki 00014, Finland;
authors.forename: Harri
authors.initials: H
authors.lastname: Nurmi
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg, Heidelberg 69120, Germany; Department of Vascular Biology and Tumor Angiogenesis, Heidelberg University, Mannheim 68167, Germany;
authors.forename: Sila
authors.initials: S
authors.lastname: Appak
authors.affiliation: Department of Oncology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Epalinges CH-1066, Switzerland;
authors.forename: Amélie
authors.initials: A
authors.lastname: Sabine
authors.affiliation: Department of Oncology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Epalinges CH-1066, Switzerland;
authors.forename: Esther
authors.initials: E
authors.lastname: Bovay
authors.affiliation: Translational Cancer Biology Program, University of Helsinki, Helsinki 00014, Finland;
authors.forename: Emilia A
authors.initials: EA
authors.lastname: Korhonen
authors.affiliation: FIRC Institute of Molecular Oncology, Milan 20139, Italy; Department of Biotechnological and Biomolecular Sciences, University of Milan, Milan 20129, Italy;
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Orsenigo
authors.affiliation: Biomedicum Imaging Unit, Biomedicum Helsinki, University of Helsinki, Helsinki 00014, Finland;
authors.forename: Marja
authors.initials: M
authors.lastname: Lohela
authors.affiliation: Translational Cancer Biology Program, University of Helsinki, Helsinki 00014, Finland;
authors.forename: Gabriela
authors.initials: G
authors.lastname: D'Amico
authors.affiliation: Translational Cancer Biology Program, University of Helsinki, Helsinki 00014, Finland;
authors.forename: Tanja
authors.initials: T
authors.lastname: Holopainen
authors.affiliation: MedImmune, Gaithersburg, Maryland 20878, USA;
authors.forename: Ching Ching
authors.initials: CC
authors.lastname: Leow
authors.affiliation: FIRC Institute of Molecular Oncology, Milan 20139, Italy; Department of Biotechnological and Biomolecular Sciences, University of Milan, Milan 20129, Italy;
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Dejana
authors.affiliation: Department of Oncology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Epalinges CH-1066, Switzerland; Swiss Institute for Cancer Research, École Polytechnique Fédérale de Lausanne, Lausanne CH-1066, Switzerland.
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Petrova
authors.affiliation: Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg, Heidelberg 69120, Germany; Department of Vascular Biology and Tumor Angiogenesis, Heidelberg University, Mannheim 68167, Germany;
authors.forename: Hellmut G
authors.initials: HG
authors.lastname: Augustin
authors.affiliation: Wihuri Research Institute, Translational Cancer Biology Program, University of Helsinki, Helsinki 00014, Finland;
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
mesh_terms: D042702:Angiopoietin-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D004622:Embryo, Mammalian; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D017353:Gene Deletion; D007365:Intercellular Junctions / Q000502:physiology*; D042583:Lymphangiogenesis / Q000502:physiology; D008221:Lymphoid Tissue / Q000196:embryology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation
chemical_list: D042702:Angiopoietin-2; D015820:Cadherins
keywords: VE-cadherin; angiopoietin 2; junction; lymphatic