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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\u2013extracellular matrix adhesions and destabilized cell\u2013cell 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\u2013CCM2 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.<\/jats:p>","DOI":"10.1242\/jcs.216093","type":"journal-article","created":{"date-parts":[[2018,7,20]],"date-time":"2018-07-20T13:35:31Z","timestamp":1532093731000},"source":"Crossref","is-referenced-by-count":61,"title":["The CCM1\u2013CCM2 complex controls complementary functions of ROCK1 and ROCK2 that are required for endothelial integrity"],"prefix":"10.1242","volume":"131","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5562-0835","authenticated-orcid":false,"given":"Justyna","family":"Lisowska","sequence":"first","affiliation":[{"name":"INSERM U1209, Institute for Advanced Biosciences 1 , F-38700 La Tronche , France"},{"name":"Universit\u00e9 Grenoble Alpes 2 , F-38042 Grenoble , France"},{"name":"CNRS UMR 5309, Institute for Advanced Biosciences 3 , F-38700 La Tronche , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia 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