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

Dev Cell. 2015 Jan 26;32(2):181-90. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Calcium-Binding Proteins
  • Cell Adhesion / physiology
  • Cell Movement / genetics
  • Cell Movement / physiology*
  • Central Nervous System Neoplasms / metabolism
  • EGF Family of Proteins
  • 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*
  • Mechanotransduction, Cellular / physiology
  • Membrane Proteins / metabolism
  • Mice
  • Neovascularization, Pathologic / metabolism*
  • Nerve Tissue Proteins / metabolism
  • Proteins / metabolism*
  • RNA, Small Interfering / genetics
  • Signal Transduction / physiology
  • Zebrafish
  • Zebrafish Proteins / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Calcium-Binding Proteins
  • EGF Family of Proteins
  • Egfl7 protein, mouse
  • Integrin beta1
  • Itgb1bp1 protein, mouse
  • Klf2 Protein, zebrafish
  • Klf2 protein, mouse
  • Kruppel-Like Transcription Factors
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Proteins
  • RNA, Small Interfering
  • Zebrafish Proteins