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Dev Cell. 2015 Jan 26;32(2):181-90. doi: 10.1016/j.devcel.2014.12.016.

Regulation of β1 integrin-Klf2-mediated angiogenesis by CCM proteins.

Author information

1
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.
2
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.
3
Max Delbrück Center for Molecular Medicine Berlin, Robert-Rössle Strasse 10, 13125 Berlin, Germany.
4
Department of Neurosurgery, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany.
5
INSERM U1161, 75010 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Génétique et Physiopathologie des Maladies Cérébro-Vasculaires UMR-S1161, 75010 Paris, France.
6
Institute for Prophylaxis and Epidemiology of Cardiovascular Diseases, Ludwig-Maximilians-University Munich, Pettenkoferstrasse 8a, 80336 Munich, Germany.
7
Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstr. 108, 01307 Dresden, Germany.
8
Institute for Molecular Biology, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
9
Institute of Genetics and Molecular and Cellular Biology (IGBMC), CNRS/INSERM/UdS, BP.10142, 67400 Illkirch, France.
10
Department on Medicine III, Cardiology, Heidelberg University Hospital, 69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, 69120 Heidelberg, Germany.
11
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.
12
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.
13
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.

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.

PMID:
25625207
DOI:
10.1016/j.devcel.2014.12.016
[Indexed for MEDLINE]
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