title: Regulation of β1 integrin-Klf2-mediated angiogenesis by CCM proteins.
abstract: Mechanotransduction pathways are activated in response to biophysical stimuli during the development or homeostasis of organs and tissues. In zebrafish, the blood-flow-sensitive transcription factor Klf2a promotes VEGF-dependent angiogenesis. However, the means by which the Klf2a mechanotransduction pathway is regulated to prevent continuous angiogenesis remain unknown. Here we report that the upregulation of klf2 mRNA causes enhanced egfl7 expression and angiogenesis signaling, which underlies cardiovascular defects associated with the loss of cerebral cavernous malformation (CCM) proteins in the zebrafish embryo. Using CCM-protein-depleted human umbilical vein endothelial cells, we show that the misexpression of KLF2 mRNA requires the extracellular matrix-binding receptor β1 integrin and occurs in the absence of blood flow. Downregulation of β1 integrin rescues ccm mutant cardiovascular malformations in zebrafish. Our work reveals a β1 integrin-Klf2-Egfl7-signaling pathway that is tightly regulated by CCM proteins. This regulation prevents angiogenic overgrowth and ensures the quiescence of endothelial cells.
authors.affiliation: Institute for Biochemistry and Biology, Potsdam University, Karl-Liebknecht-Strasse 24-25, Building 26, 14476 Potsdam, Germany; Institute for Molecular Biology, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Renz
authors.affiliation: Institute for Biochemistry and Biology, Potsdam University, Karl-Liebknecht-Strasse 24-25, Building 26, 14476 Potsdam, Germany; Institute for Molecular Biology, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
authors.forename: Cécile
authors.initials: C
authors.lastname: Otten
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U823, Institute Albert Bonniot, 38042 Grenoble, France; Équipes de Recherche Labellisées (ERL) Centre National de la Recherche Scientifique (CNRS) 5284, 38042 Grenoble, France; Université Joseph Fourier, 38042 Grenoble, France.
authors.forename: Eva
authors.initials: E
authors.lastname: Faurobert
authors.affiliation: Max Delbrück Center for Molecular Medicine Berlin, Robert-Rössle Strasse 10, 13125 Berlin, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Rudolph
authors.affiliation: Department of Neurosurgery, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: INSERM U1161, 75010 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Génétique et Physiopathologie des Maladies Cérébro-Vasculaires UMR-S1161, 75010 Paris, France.
authors.forename: Gwénola
authors.initials: G
authors.lastname: Boulday
authors.affiliation: Institute for Prophylaxis and Epidemiology of Cardiovascular Diseases, Ludwig-Maximilians-University Munich, Pettenkoferstrasse 8a, 80336 Munich, Germany.
authors.forename: Johan
authors.initials: J
authors.lastname: Duchene
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstr. 108, 01307 Dresden, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Mickoleit
authors.affiliation: Institute for Molecular Biology, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
authors.forename: Ann-Christin
authors.initials: AC
authors.lastname: Dietrich
authors.affiliation: Institute of Genetics and Molecular and Cellular Biology (IGBMC), CNRS/INSERM/UdS, BP.10142, 67400 Illkirch, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Ramspacher
authors.affiliation: Institute of Genetics and Molecular and Cellular Biology (IGBMC), CNRS/INSERM/UdS, BP.10142, 67400 Illkirch, France.
authors.forename: Emily
authors.initials: E
authors.lastname: Steed
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U823, Institute Albert Bonniot, 38042 Grenoble, France; Équipes de Recherche Labellisées (ERL) Centre National de la Recherche Scientifique (CNRS) 5284, 38042 Grenoble, France; Université Joseph Fourier, 38042 Grenoble, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Manet-Dupé
authors.affiliation: Department on Medicine III, Cardiology, Heidelberg University Hospital, 69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, 69120 Heidelberg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Benz
authors.affiliation: Department on Medicine III, Cardiology, Heidelberg University Hospital, 69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, 69120 Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Hassel
authors.affiliation: Institute of Genetics and Molecular and Cellular Biology (IGBMC), CNRS/INSERM/UdS, BP.10142, 67400 Illkirch, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Vermot
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstr. 108, 01307 Dresden, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Huisken
authors.affiliation: INSERM U1161, 75010 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Génétique et Physiopathologie des Maladies Cérébro-Vasculaires UMR-S1161, 75010 Paris, France; Groupe hospitalier Saint-Louis Lariboisière-Fernand-Widal, Assistance Publique - Hôpitaux de Paris, Service de génétique moléculaire neurovasculaire, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l'Oeil (CERVCO), 75010 Paris, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Tournier-Lasserve
authors.affiliation: Department of Human Genetics, University Medicine Greifswald, Fleischmannstr. 42-44, 17475 Greifswald, Germany; Interfaculty Institute for Genetics and Functional Genomics, Division of Human Genetics, Ernst-Moritz-Arndt University Greifswald, 17475 Greifswald, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Felbor
authors.affiliation: Department of Neurosurgery, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Sure
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U823, Institute Albert Bonniot, 38042 Grenoble, France; Équipes de Recherche Labellisées (ERL) Centre National de la Recherche Scientifique (CNRS) 5284, 38042 Grenoble, France; Université Joseph Fourier, 38042 Grenoble, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Albiges-Rizo
authors.affiliation: Institute for Biochemistry and Biology, Potsdam University, Karl-Liebknecht-Strasse 24-25, Building 26, 14476 Potsdam, Germany; Institute for Molecular Biology, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany. Electronic address: salim.seyfried@uni-potsdam.de.
authors.forename: Salim
authors.initials: S
authors.lastname: Abdelilah-Seyfried
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002135:Calcium-Binding Proteins; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D016543:Central Nervous System Neoplasms / Q000378:metabolism; D066255:EGF Family of Proteins; D020786:Hemangioma, Cavernous, Central Nervous System / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D040542:Mechanotransduction, Cellular / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; D066255:EGF Family of Proteins; C479627:Egfl7 protein, mouse; D019012:Integrin beta1; C114243:Itgb1bp1 protein, mouse; C000597129:Klf2 Protein, zebrafish; C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; D034741:RNA, Small Interfering; D029961:Zebrafish Proteins