title: Angiomotin regulates endothelial cell migration during embryonic angiogenesis.
abstract: The development of the embryonic vascular system into a highly ordered network requires precise control over the migration and branching of endothelial cells (ECs). We have previously identified angiomotin (Amot) as a receptor for the angiogenesis inhibitor angiostatin. Furthermore, DNA vaccination targeting Amot inhibits angiogenesis and tumor growth. However, little is known regarding the role of Amot in physiological angiogenesis. We therefore investigated the role of Amot in embryonic neovascularization during zebrafish and mouse embryogenesis. Here we report that knockdown of Amot in zebrafish reduced the number of filopodia of endothelial tip cells and severely impaired the migration of intersegmental vessels. We further show that 75% of Amot knockout mice die between embryonic day 11 (E11) and E11.5 and exhibit severe vascular insufficiency in the intersomitic region as well as dilated vessels in the brain. Furthermore, using ECs differentiated from embryonic stem (ES) cells, we demonstrate that Amot-deficient cells have intact response to vascular endothelial growth factor (VEGF) in regard to differentiation and proliferation. However, the chemotactic response to VEGF was abolished in Amot-deficient cells. We provide evidence that Amot is important for endothelial polarization during migration and that Amot controls Rac1 activity in endothelial and epithelial cells. Our data demonstrate a critical role for Amot during vascular patterning and endothelial polarization.
authors: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, SE-17176 Stockholm, Sweden.
authors: Karin
authors: K
authors: Aase
authors: Mira
authors: M
authors: Ernkvist
authors: Lwaki
authors: L
authors: Ebarasi
authors: Lars
authors: L
authors: Jakobsson
authors: Arindam
authors: A
authors: Majumdar
authors: Chunling
authors: C
authors: Yi
authors: Olivier
authors: O
authors: Birot
authors: Yue
authors: Y
authors: Ming
authors: Anders
authors: A
authors: Kvanta
authors: Dan
authors: D
authors: Edholm
authors: Pontus
authors: P
authors: Aspenström
authors: Joseph
authors: J
authors: Kissil
authors: Lena
authors: L
authors: Claesson-Welsh
authors: Akihiko
authors: A
authors: Shimono
authors: Lars
authors: L
authors: Holmgren
mesh_terms: D000091082:Angiomotins; D000818:Animals; D001483:Base Sequence; D019521:Body Patterning / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D005260:Female; D017353:Gene Deletion; D020868:Gene Silencing; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D011247:Pregnancy; D011554:Pseudopodia / Q000648:ultrastructure; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics / Q000502:physiology*; D029961:Zebrafish Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: C511047:Amot protein, mouse; D000091082:Angiomotins; D017931:DNA Primers; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D029961:Zebrafish Proteins; D020830:rac1 GTP-Binding Protein
references: Development. 2007 Mar;134(5):839-44
references: 17251261
references: EMBO Rep. 2007 Feb;8(2):158-64
references: 17235357
references: J Biol Chem. 2000 Jun 16;275(24):18040-5
references: 10748121
references: J Cell Biol. 2001 Mar 19;152(6):1247-54
references: 11257124
references: J Biol Chem. 2001 Sep 14;276(37):35060-70
references: 11431473
references: EMBO J. 2001 Nov 15;20(22):6327-36
references: 11707404
references: Development. 2002 Feb;129(4):973-82
references: 11861480
references: Dev Biol. 2002 Aug 15;248(2):307-18
references: 12167406
references: Nat Med. 2002 Sep;8(9):918-21
references: 12205444
references: Gene. 2002 Sep 18;298(1):69-77
references: 12406577
references: Semin Cell Dev Biol. 2002 Dec;13(6):515-22
references: 12468255
references: Invest Ophthalmol Vis Sci. 2003 Jan;44(1):403-8
references: 12506102
references: Nat Genet. 2003 Mar;33(3):401-6
references: 12590264
references: Curr Biol. 2003 Apr 1;13(7):613-7
references: 12676095
references: J Cell Biol. 2003 Jun 23;161(6):1163-77
references: 12810700
references: J Cell Sci. 2003 Sep 15;116(Pt 18):3803-10
references: 12902404
references: Development. 2003 Nov;130(21):5281-90
references: 12954720
references: Oncogene. 2004 Feb 19;23(7):1469-73
references: 14730344
references: Physiology (Bethesda). 2004 Oct;19:300-8
references: 15381759
references: Annu Rev Cell Biol. 1986;2:337-65
references: 3548771
references: Cell. 1995 Apr 7;81(1):53-62
references: 7536630
references: Nature. 1996 Apr 4;380(6573):435-9
references: 8602241
references: Nature. 1996 Apr 4;380(6573):439-42
references: 8602242
references: Cell. 1996 Jun 14;85(6):863-73
references: 8681381
references: Blood. 1996 Nov 1;88(9):3424-31
references: 8896407
references: Nature. 1997 Apr 17;386(6626):671-4
references: 9109485
references: Arterioscler Thromb Vasc Biol. 1997 Sep;17(9):1623-9
references: 9327754
references: Cell. 1998 Mar 20;92(6):735-45
references: 9529250
references: Cell. 1998 May 29;93(5):661-4
references: 9630209
references: J Cell Biol. 1999 Mar 22;144(6):1235-44
references: 10087266
references: Curr Top Dev Biol. 2004;62:127-52
references: 15522741
references: J Biol Chem. 2005 Oct 14;280(41):34859-69
references: 16043488
references: Nat Rev Mol Cell Biol. 2006 May;7(5):359-71
references: 16633338
references: FEBS J. 2006 May;273(9):2000-11
references: 16640563
references: Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6554-9
references: 16617120
references: Cell. 2006 May 5;125(3):535-48
references: 16678097
references: Dev Cell. 2006 May;10(5):625-34
references: 16678777
references: Acta Ophthalmol Scand. 2006 Jun;84(3):282-8
references: 16704684
references: Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9208-13
references: 16754857
references: Physiology (Bethesda). 2006 Dec;21:388-95
references: 17119151
references: Arterioscler Thromb Vasc Biol. 2000 Jun;20(6):1443-51
references: 10845856