TY  - JOUR
A1  - Lisowska, Justyna
A1  - Rödel, Claudia Jasmin
A1  - Manet, Sandra
A1  - Miroshnikova, Yekaterina A.
A1  - Boyault, Cyril
A1  - Planus, Emmanuelle
A1  - De Mets, Richard
A1  - Lee, Hsiao-Hui
A1  - Destaing, Olivier
A1  - Mertani, Hichem
A1  - Boulday, Gwenola
A1  - Tournier-Lasserve, Elisabeth
A1  - Balland, Martial
A1  - Abdelilah-Seyfried, Salim
A1  - Albiges-Rizo, Corinne
A1  - Faurobert, Eva
T1  - The CCM1-CCM2 complex controls complementary functions of ROCK1 and ROCK2 that are required for endothelial integrity
JF  - Journal of cell science
N2  - 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.
KW  - CCM
KW  - ROCK
KW  - Endothelial integrity
KW  - Mechanotransduction
Y1  - 2018
U6  - https://doi.org/10.1242/jcs.216093
SN  - 0021-9533
SN  - 1477-9137
VL  - 131
IS  - 15
PB  - Company biologists LTD
CY  - Cambridge
ER  -