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

Item Type:Article
Title:Regulation of β1 integrin-Klf2-mediated angiogenesis by CCM proteins
Creators Name:Renz, M. and Otten, C. and Faurobert, E. and Rudolph, F. and Zhu, Y. and Boulday, G. and Duchene, J. and Mickoleit, M. and Dietrich, A.C. and Ramspacher, C. and Steed, E. and Manet-Dupe, S. and Benz, A. and Hassel, D. and Vermot, J. and Huisken, J. and Tournier-Lasserve, E. and Felbor, U. and Sure, U. and Albiges-Rizo, C. and Abdelilah-Seyfried, S.
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 {beta}1 integrin and occurs in the absence of blood flow. Downregulation of {beta}1 integrin rescues ccm mutant cardiovascular malformations in zebrafish. Our work reveals a {beta}1 integrin-Klf2-Egfl7-signaling pathway that is tightly regulated by CCM proteins. This regulation prevents angiogenic overgrowth and ensures the quiescence of endothelial cells.
Keywords:CD29 Antigens, Cell Adhesion, Cell Movement, Central Nervous System Neoplasms, Central Nervous System Cavernous Hemangioma, Human Umbilical Vein Endothelial Cells, Kruppel-Like Transcription Factors, Cellular Mechanotransduction, Membrane Proteins, Pathologic Neovascularization, Nerve Tissue Proteins, Proteins, Small Interfering RNA, Signal Transduction, Animals, Zebrafish
Source:Developmental Cell
Publisher:Cell Press / Elsevier
Page Range:181-190
Date:26 January 2015
Additional Information:Copyright © 2015 Elsevier Inc. All rights reserved.
Official Publication:https://doi.org/10.1016/j.devcel.2014.12.016
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