Cerebral Cavernous Malformation 1/2 complex controls ROCK1 and ROCK2 complementary functions for endothelial integrity
- Lisowska, J., Rödel, C.J., Manet, S., Miroshnikova, Y.A., Boyault, C., Planus, E., De Mets, R., Lee, H.H., Destaing, O., Mertani, H., Boulday, G., Tournier-Lasserve, E., Balland, M., Abdelilah-Seyfried, S., Albiges-Rizo, C., Faurobert, E.
- Journal of Cell Science 131(15): (Journal)
- Registered Authors
- Abdelilah-Seyfried, Salim
- CCM, Endothelial integrity, Mechanotransduction, ROCK
- MeSH Terms
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Blotting, Western
- Carrier Proteins/genetics
- Carrier Proteins/metabolism*
- Endothelial Cells/cytology
- Endothelial Cells/metabolism*
- Flow Cytometry
- Fluorescent Antibody Technique
- Human Umbilical Vein Endothelial Cells
- KRIT1 Protein/genetics
- KRIT1 Protein/metabolism*
- Reverse Transcriptase Polymerase Chain Reaction
- rho-Associated Kinases/genetics
- rho-Associated Kinases/metabolism*
- 30030370 Full text @ J. Cell Sci.
Lisowska, J., Rödel, C.J., Manet, S., Miroshnikova, Y.A., Boyault, C., Planus, E., De Mets, R., Lee, H.H., Destaing, O., Mertani, H., Boulday, G., Tournier-Lasserve, E., Balland, M., Abdelilah-Seyfried, S., Albiges-Rizo, C., Faurobert, E. (2018) Cerebral Cavernous Malformation 1/2 complex controls ROCK1 and ROCK2 complementary functions for endothelial integrity. Journal of Cell Science. 131(15).
Endothelial integrity relies on a mechanical crosstalk between intercellular and cell-matrix interactions. This crosstalk is compromised in hemorrhagic vascular lesions of patients carrying loss-of-function mutations in cerebral cavernous malformation (CCM) genes. RhoA/ROCK-dependent cytoskeletal remodeling is central to the disease, as it causes unbalanced cell adhesion towards increased cell-extracellular matrix adhesions and destabilized cell-cell junctions. This study reveals that CCM proteins directly orchestrate ROCK1 and ROCK2 complementary roles on the mechanics of the endothelium. CCM proteins act as a scaffold, promoting ROCK2 interactions with VE-cadherin and limiting ROCK1 kinase activity. Loss of CCM1 (also known as KRIT1) produces excessive ROCK1-dependent actin stress fibers and destabilizes intercellular junctions. Silencing of ROCK1 but not ROCK2 restores the adhesive and mechanical homeostasis of CCM1 and CCM2-depleted endothelial monolayers, and rescues the cardiovascular defects of ccm1 mutant zebrafish embryos. Conversely, knocking down Rock2 but not Rock1 in wild-type zebrafish embryos generates defects reminiscent of the ccm1 mutant phenotypes. Our study uncovers the role of the CCM1-CCM2 complex in controlling ROCK1 and ROCK2 to preserve endothelial integrity and drive heart morphogenesis. Moreover, it solely identifies the ROCK1 isoform as a potential therapeutic target for the CCM disease.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes