CCM1-ICAP-1 complex controls β1 integrin-dependent endothelial contractility and fibronectin remodeling

J Cell Biol. 2013 Aug 5;202(3):545-61. doi: 10.1083/jcb.201303044.


The endothelial CCM complex regulates blood vessel stability and permeability. Loss-of-function mutations in CCM genes are responsible for human cerebral cavernous malformations (CCMs), which are characterized by clusters of hemorrhagic dilated capillaries composed of endothelium lacking mural cells and altered sub-endothelial extracellular matrix (ECM). Association of the CCM1/2 complex with ICAP-1, an inhibitor of β1 integrin, prompted us to investigate whether the CCM complex interferes with integrin signaling. We demonstrate that CCM1/2 loss resulted in ICAP-1 destabilization, which increased β1 integrin activation and led to increased RhoA-dependent contractility. The resulting abnormal distribution of forces led to aberrant ECM remodeling around lesions of CCM1- and CCM2-deficient mice. ICAP-1-deficient vessels displayed similar defects. We demonstrate that a positive feedback loop between the aberrant ECM and internal cellular tension led to decreased endothelial barrier function. Our data support that up-regulation of β1 integrin activation participates in the progression of CCM lesions by destabilizing intercellular junctions through increased cell contractility and aberrant ECM remodeling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion
  • Cells, Cultured
  • Fibronectins / metabolism*
  • Human Umbilical Vein Endothelial Cells / cytology
  • Human Umbilical Vein Endothelial Cells / metabolism*
  • Humans
  • Integrin beta1 / metabolism*
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • KRIT1 Protein
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Microtubule-Associated Proteins / deficiency
  • Microtubule-Associated Proteins / metabolism*
  • Models, Biological
  • Proto-Oncogene Proteins / deficiency
  • Proto-Oncogene Proteins / metabolism*


  • Fibronectins
  • ICAP-1 protein, mouse
  • Integrin beta1
  • Intracellular Signaling Peptides and Proteins
  • KRIT1 Protein
  • Krit1 protein, mouse
  • Microtubule-Associated Proteins
  • Proto-Oncogene Proteins