title: PP2A regulatory subunit Bα controls endothelial contractility and vessel lumen integrity via regulation of HDAC7.
abstract: To supply tissues with nutrients and oxygen, the cardiovascular system forms a seamless, hierarchically branched, network of lumenized tubes. Here, we show that maintenance of patent vessel lumens requires the Bα regulatory subunit of protein phosphatase 2A (PP2A). Deficiency of Bα in zebrafish precludes vascular lumen stabilization resulting in perfusion defects. Similarly, inactivation of PP2A-Bα in cultured ECs induces tubulogenesis failure due to alteration of cytoskeleton dynamics, actomyosin contractility and maturation of cell-extracellular matrix (ECM) contacts. Mechanistically, we show that PP2A-Bα controls the activity of HDAC7, an essential transcriptional regulator of vascular stability. In the absence of PP2A-Bα, transcriptional repression by HDAC7 is abrogated leading to enhanced expression of the cytoskeleton adaptor protein ArgBP2. ArgBP2 hyperactivates RhoA causing inadequate rearrangements of the EC actomyosin cytoskeleton. This study unravels the first specific role for a PP2A holoenzyme in development: the PP2A-Bα/HDAC7/ArgBP2 axis maintains vascular lumens by balancing endothelial cytoskeletal dynamics and cell-matrix adhesion.
authors: Laboratory of Protein Signaling and Interactions, Interdisciplinary Cluster for Applied Genoproteomics (GIGA-R), University of Liège, Sart-Tilman, Belgium.
authors: Maud
authors: M
authors: Martin
authors: Ilse
authors: I
authors: Geudens
authors: Jonathan
authors: J
authors: Bruyr
authors: Michael
authors: M
authors: Potente
authors: Anouk
authors: A
authors: Bleuart
authors: Marielle
authors: M
authors: Lebrun
authors: Nicolas
authors: N
authors: Simonis
authors: Christophe
authors: C
authors: Deroanne
authors: Jean-Claude
authors: JC
authors: Twizere
authors: Philippe
authors: P
authors: Soubeyran
authors: Paul
authors: P
authors: Peixoto
authors: Denis
authors: D
authors: Mottet
authors: Veerle
authors: V
authors: Janssens
authors: Wolf-Karsten
authors: WK
authors: Hofmann
authors: Filip
authors: F
authors: Claes
authors: Peter
authors: P
authors: Carmeliet
authors: Richard
authors: R
authors: Kettmann
authors: Holger
authors: H
authors: Gerhardt
authors: Franck
authors: F
authors: Dequiedt
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D003094:Collagen; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006655:Histone Deacetylases / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007797:Laminin; D018613:Microscopy, Confocal; D018919:Neovascularization, Physiologic / Q000502:physiology*; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D011509:Proteoglycans; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins; D014654:Vascular Patency / Q000235:genetics / Q000502:physiology*; D015027:Zebrafish
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004338:Drug Combinations; D018398:Homeodomain Proteins; D007797:Laminin; D011509:Proteoglycans; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C490755:SORBS2 protein, human; C059485:matrigel; D003094:Collagen; D054648:Protein Phosphatase 2; C543273:HDAC7 protein, human; D006655:Histone Deacetylases
references: Nat Immunol. 2003 Dec;4(12):1238-46
references: 14608381
references: J Neurosci. 1997 Aug 1;17(15):5726-37
references: 9221771
references: Semin Cell Dev Biol. 2011 Dec;22(9):993-1004
references: 21624487
references: Development. 2005 Dec;132(23):5199-209
references: 16251212
references: J Neurochem. 2007 May;101(4):959-71
references: 17394530
references: Otolaryngol Head Neck Surg. 1999 Oct;121(4):463-8
references: 10504605
references: J Biol Chem. 1999 Sep 3;274(36):25490-8
references: 10464280
references: Development. 2011 Nov;138(21):4569-83
references: 21965610
references: Cell Mol Life Sci. 2010 Oct;67(19):3209-18
references: 20490602
references: J Cell Biol. 2011 Oct 17;195(2):231-43
references: 21987638
references: J Cell Biol. 2012 Aug 20;198(4):481-9
references: 22908306
references: Cell. 2011 Sep 16;146(6):873-87
references: 21925313
references: Nature. 2006 Jul 27;442(7101):453-6
references: 16799567
references: Dev Cell. 2011 Apr 19;20(4):563-71
references: 21497766
references: PLoS One. 2010 Oct 25;5(10):e13612
references: 21049044
references: Cell Adh Migr. 2009 Apr-Jun;3(2):167-70
references: 19262174
references: J Cell Biochem. 2006 Jul 1;98(4):931-53
references: 16475161
references: J Biol Chem. 2007 Oct 5;282(40):29122-9
references: 17684019
references: J Vasc Res. 2011;48(5):369-85
references: 21464572
references: Nat Cell Biol. 1999 Jul;1(3):136-43
references: 10559899
references: Dev Cell. 2009 Oct;17(4):505-15
references: 19853564
references: FEBS J. 2013 Jan;280(2):644-61
references: 22443683
references: Curr Biol. 2004 Apr 20;14(8):691-6
references: 15084284
references: J Cell Biol. 2002 Nov 25;159(4):673-83
references: 12446743
references: J Cell Sci. 2007 Jan 1;120(Pt 1):137-48
references: 17164291
references: Cell Signal. 2009 Dec;21(12):1727-37
references: 19720142
references: Dev Biol. 2002 Aug 15;248(2):307-18
references: 12167406
references: Dev Cell. 2011 Sep 13;21(3):506-19
references: 21871841
references: Mol Cell. 2010 Dec 22;40(6):863-76
references: 21172653
references: J Cell Sci. 2009 Apr 15;122(Pt 8):1248-57
references: 19339557
references: J Cell Sci. 2012 Sep 1;125(Pt 17):4137-46
references: 22685328
references: J Biol Chem. 2004 Mar 19;279(12):11686-95
references: 14699132
references: Nat Cell Biol. 2011 Aug 28;13(10):1265-71
references: 21874008
references: Biochem J. 2001 Feb 1;353(Pt 3):417-39
references: 11171037
references: J Cell Biol. 1995 Mar;128(6):1131-44
references: 7896877
references: Circ Res. 2007 Dec 7;101(12):1237-46
references: 17947801
references: J Clin Invest. 2005 Sep;115(9):2382-92
references: 16100571
references: Nat Rev Mol Cell Biol. 2010 Sep;11(9):633-43
references: 20729930
references: Biochem J. 2012 Jun 1;444(2):239-47
references: 22417654
references: J Cell Sci. 2008 Aug 1;121(Pt 15):2435-44
references: 18650496
references: Dev Cell. 2009 Feb;16(2):222-31
references: 19217424
references: Development. 2002 Jun;129(12):3009-19
references: 12050147
references: J Cell Sci. 2009 Jun 1;122(Pt 11):1812-22
references: 19435802
references: Genes Dev. 2009 Jul 15;23(14):1639-49
references: 19605686
references: Mol Cell. 2011 Feb 18;41(4):471-9
references: 21329884
references: Dev Biol. 2008 Apr 15;316(2):312-22
references: 18342303
references: Mol Cell. 2009 Mar 13;33(5):537-45
references: 19285938
references: J Cell Biol. 1995 Jul;130(2):355-68
references: 7542246
references: Oncogene. 2007 Aug 13;26(37):5450-67
references: 17694086
references: Dev Biol. 1999 Jul 15;211(2):255-67
references: 10395786
references: Cancer Cell. 2010 Dec 14;18(6):641-54
references: 21156286
references: Development. 2003 Nov;130(21):5281-90
references: 12954720
references: PLoS Genet. 2011 Aug;7(8):e1002227
references: 21852958
references: EMBO J. 1999 Feb 1;18(3):578-85
references: 9927417
references: Mol Cell Biol. 2000 Feb;20(3):1021-9
references: 10629059
references: Microvasc Res. 2011 Jan;81(1):34-43
references: 20849862
references: Microvasc Res. 2006 May;71(3):152-62
references: 16650878
references: Development. 2010 Sep;137(18):3119-28
references: 20736288
references: Curr Biol. 1996 Oct 1;6(10):1279-89
references: 8939572
references: Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1731-6
references: 15659545
references: Cell Motil Cytoskeleton. 2009 Nov;66(11):1017-29
references: 19598236
references: Mol Cell. 2010 Mar 12;37(5):633-42
references: 20227368
references: J Biol Chem. 2006 Apr 28;281(17):11627-36
references: 16513648
references: Am J Physiol Regul Integr Comp Physiol. 2007 Sep;293(3):R963-73
references: 17609315
references: Cell Struct Funct. 2002 Feb;27(1):1-7
references: 11937713
references: Nat Rev Mol Cell Biol. 2007 Jun;8(6):464-78
references: 17522591
references: J Biol Chem. 2010 Sep 24;285(39):29863-73
references: 20663872
references: Proc Natl Acad Sci U S A. 2008 Mar 25;105(12):4727-32
references: 18339811
references: Trends Cell Biol. 1997 Sep;7(9):342-7
references: 17708978
references: Biochem J. 2003 Feb 15;370(Pt 1):29-34
references: 12475393
references: FEBS J. 2013 Jan;280(2):662-73
references: 22583914
references: Cell. 2006 Jul 28;126(2):321-34
references: 16873063