Dynamic regulation of the cerebral cavernous malformation pathway controls vascular stability and growth

Dev Cell. 2012 Aug 14;23(2):342-55. doi: 10.1016/j.devcel.2012.06.004.


Cardiovascular growth must balance stabilizing signals required to maintain endothelial connections and network integrity with destabilizing signals that enable individual endothelial cells to migrate and proliferate. The cerebral cavernous malformation (CCM) signaling pathway utilizes the adaptor protein CCM2 to strengthen endothelial cell junctions and stabilize vessels. Here we identify a CCM2 paralog, CCM2L, that is expressed selectively in endothelial cells during periods of active cardiovascular growth. CCM2L competitively blocks CCM2-mediated stabilizing signals biochemically, in cultured endothelial cells, and in developing mice. Loss of CCM2L reduces endocardial growth factor expression and impairs tumor growth and wound healing. Our studies identify CCM2L as a molecular mechanism by which endothelial cells coordinately regulate vessel stability and growth during cardiovascular development, as well as postnatal vessel growth.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Central Nervous System Vascular Malformations / embryology
  • Central Nervous System Vascular Malformations / genetics
  • Central Nervous System Vascular Malformations / metabolism*
  • Embryo, Mammalian / blood supply
  • Embryo, Mammalian / metabolism
  • Gene Expression Regulation, Developmental
  • Intercellular Junctions / metabolism
  • KRIT1 Protein
  • Mice
  • Mice, Knockout
  • Microfilament Proteins / chemistry
  • Microfilament Proteins / deficiency
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism*
  • Microtubule-Associated Proteins / chemistry
  • Microtubule-Associated Proteins / deficiency
  • Microtubule-Associated Proteins / metabolism*
  • Molecular Sequence Data
  • Neovascularization, Pathologic*
  • Protein Binding
  • Proto-Oncogene Proteins / metabolism
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Signal Transduction


  • CCM2L protein, mouse
  • KRIT1 Protein
  • Krit1 protein, mouse
  • Microfilament Proteins
  • Microtubule-Associated Proteins
  • Proto-Oncogene Proteins
  • osmosensing scaffold for MEKK3 protein, mouse