Regulation of β1 Integrin-Klf2-Mediated Angiogenesis by CCM Proteins

• Published in: Developmental cell 2015-01, Vol.32 (2), p.181-190
• Main Authors: Renz, Marc, Otten, Cécile, Faurobert, Eva, Rudolph, Franziska, Zhu, Yuan, Boulday, Gwénola, Duchene, Johan, Mickoleit, Michaela, Dietrich, Ann-Christin, Ramspacher, Caroline, Steed, Emily, Manet-Dupé, Sandra, Benz, Alexander, Hassel, David, Vermot, Julien, Huisken, Jan, Tournier-Lasserve, Elisabeth, Felbor, Ute, Sure, Ulrich, Albiges-Rizo, Corinne, Abdelilah-Seyfried, Salim
• Format: Article
• Language: English
• Subjects: Animals; Cell Adhesion - physiology; Cell Movement - genetics; Cell Movement - physiology; Central Nervous System Neoplasms - metabolism; Development Biology; Hemangioma, Cavernous, Central Nervous System - genetics; Hemangioma, Cavernous, Central Nervous System - metabolism; Human Umbilical Vein Endothelial Cells - cytology; Human Umbilical Vein Endothelial Cells - metabolism; Integrin beta1 - metabolism; Kruppel-Like Transcription Factors - metabolism; Life Sciences; Mechanotransduction, Cellular - physiology; Membrane Proteins - metabolism; Mice; Morphogenesis; Neovascularization, Pathologic - metabolism; Nerve Tissue Proteins - metabolism; Proteins - metabolism; RNA, Small Interfering - genetics; Signal Transduction - physiology; Zebrafish; Zebrafish Proteins - metabolism
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2014.12.016

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. [Display omitted] •Loss of cerebral cavernous malformation proteins causes an upregulation of Klf2•Upregulation of Klf2 requires β1 integrin and occurs in the absence of blood flow•Klf2 positively regulates egfl7 expression and promotes angiogenesis•Aberrant angiogenesis signaling underlies ccm mutant cardiovascular defects Renz et al. identify the CCM complex as a key regulator of a β1 integrin-Klf2-Egfl7 mechanotransduction pathway in zebrafish. This regulation prevents angiogenic overgrowth and ensures the quiescence and differentiation of endothelial and endocardial cells.