The CCM1-CCM2 complex controls complementary functions of ROCK1 and ROCK2 that are required for endothelial integrity

• Published in: Journal of cell science Vol. 131; no. 15
• Main Authors: Lisowska, Justyna, Rödel, Claudia Jasmin, Manet, Sandra, Miroshnikova, Yekaterina A, Boyault, Cyril, Planus, Emmanuelle, De Mets, Richard, Lee, Hsiao-Hui, Destaing, Olivier, Mertani, Hichem, Boulday, Gwénola, Tournier-Lasserve, Elisabeth, Balland, Martial, Abdelilah-Seyfried, Salim, Albiges-Rizo, Corinne, Faurobert, Eva
• Format: Journal Article
• Language: English
• Published: England Company of Biologists 13.08.2018
• Subjects: Cell Behavior; Cellular Biology; Life Sciences; Mechanotransduction; ROCK; CCM; Endothelial integrity
• ISSN: 0021-9533; 1477-9137
• DOI: 10.1242/jcs.216093

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 mutant zebrafish embryos. Conversely, knocking down Rock2 but not Rock1 in wild-type zebrafish embryos generates defects reminiscent of the 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.