Justyna Lisowska, Claudia Jasmin Rödel, Sandra Manet, Yekaterina A. Miroshnikova, Cyril Boyault, Emmanuelle Planus, Richard De Mets, Hsiao-Hui Lee, Olivier Destaing, Hichem Mertani, Gwenola Boulday, Elisabeth Tournier-Lasserve, Martial Balland, Salim Abdelilah-Seyfried, Corinne Albiges-Rizo, Eva Faurobert
- 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.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.…
MetadatenAuthor details: | Justyna LisowskaORCiD, Claudia Jasmin RödelORCiD, Sandra Manet, Yekaterina A. MiroshnikovaORCiD, Cyril BoyaultORCiD, Emmanuelle PlanusORCiD, Richard De Mets, Hsiao-Hui Lee, Olivier Destaing, Hichem Mertani, Gwenola BouldayORCiD, Elisabeth Tournier-Lasserve, Martial Balland, Salim Abdelilah-SeyfriedORCiDGND, Corinne Albiges-RizoORCiD, Eva FaurobertORCiD |
---|
DOI: | https://doi.org/10.1242/jcs.216093 |
---|
ISSN: | 0021-9533 |
---|
ISSN: | 1477-9137 |
---|
Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/30030370 |
---|
Title of parent work (English): | Journal of cell science |
---|
Publisher: | Company biologists LTD |
---|
Place of publishing: | Cambridge |
---|
Publication type: | Article |
---|
Language: | English |
---|
Date of first publication: | 2018/07/03 |
---|
Publication year: | 2018 |
---|
Release date: | 2021/10/20 |
---|
Tag: | CCM; Endothelial integrity; Mechanotransduction; ROCK |
---|
Volume: | 131 |
---|
Issue: | 15 |
---|
Number of pages: | 15 |
---|
Funding institution: | Agence Nationale de la Recherche (ANR)French National Research Agency (ANR); Ligue Contre le Cancer (LNCC) for Equipe labellisee Ligue 2014; Fondation pour la Recherche Medicale (FRM) for Equipe Labellisee; Fondation ARC; Ligue Regionale contre le CancerLigue nationale contre le cancer; LNCC; FRMFondation pour la Recherche Medicale; Whitaker Foundation Postdoctoral Scholarship; excellence cluster REBIRTH [SFB958]; Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [SE2016/7-2, SE2016/10-1] |
---|
Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie |
---|
DDC classification: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
---|
Peer review: | Referiert |
---|
Publishing method: | Open Access / Bronze Open-Access |
---|