TY - JOUR A1 - Renz, Marc A1 - Otten, Cecile A1 - Faurobert, Eva A1 - Rudolph, Franziska A1 - Zhu, Yuan A1 - Boulday, Gwenola A1 - Duchene, Johan A1 - Mickoleit, Michaela A1 - Dietrich, Ann-Christin A1 - Ramspacher, Caroline A1 - Steed, Emily A1 - Manet-Dupe, Sandra A1 - Benz, Alexander A1 - Hassel, David A1 - Vermot, Julien A1 - Huisken, Jan A1 - Tournier-Lasserve, Elisabeth A1 - Felbor, Ute A1 - Sure, Ulrich A1 - Albiges-Rizo, Corinne A1 - Abdelilah-Seyfried, Salim T1 - Regulation of beta 1 Integrin-Klf2-Mediated angiogenesis by CCM proteins JF - Developmental cell N2 - Mechanotransduction pathways are activated in response to biophysical stimuli during the development or homeostasis of organs and tissues. In zebrafish, the blood-flow-sensitive transcription factor Klf2a promotes VEGF-dependent angiogenesis. However, the means by which the Klf2a mechanotransduction pathway is regulated to prevent continuous angiogenesis remain unknown. Here we report that the upregulation of klf2 mRNA causes enhanced egfl7 expression and angiogenesis signaling, which underlies cardiovascular defects associated with the loss of cerebral cavernous malformation (CCM) proteins in the zebrafish embryo. Using CCM-protein-depleted human umbilical vein endothelial cells, we show that the misexpression of KLF2 mRNA requires the extracellular matrix-binding receptor beta 1 integrin and occurs in the absence of blood flow. Downregulation of beta 1 integrin rescues ccm mutant cardiovascular malformations in zebrafish. Our work reveals a beta 1 integrin-Klf2-Egfl7-signaling pathway that is tightly regulated by CCM proteins. This regulation prevents angiogenic overgrowth and ensures the quiescence of endothelial cells. Y1 - 2015 U6 - https://doi.org/10.1016/j.devcel.2014.12.016 SN - 1534-5807 SN - 1878-1551 VL - 32 IS - 2 SP - 181 EP - 190 PB - Cell Press CY - Cambridge ER - 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 - TY - JOUR A1 - Otten, Cecile A1 - Knox, Jessica A1 - Boulday, Gwenola A1 - Eymery, Mathias A1 - Haniszewski, Marta A1 - Neuenschwander, Martin A1 - Radetzki, Silke A1 - Vogt, Ingo A1 - Haehn, Kristina A1 - De Luca, Coralie A1 - Cardoso, Cecile A1 - Hamad, Sabri A1 - Igual Gil, Carla A1 - Roy, Peter A1 - Albiges-Rizo, Corinne A1 - Faurobert, Eva A1 - von Kries, Jens P. A1 - Campillos, Monica A1 - Tournier-Lasserve, Elisabeth A1 - Derry, William Brent A1 - Abdelilah-Seyfried, Salim T1 - Systematic pharmacological screens uncover novel pathways involved in cerebral cavernous malformations JF - EMBO molecular medicine N2 - Cerebral cavernous malformations (CCMs) are vascular lesions in the central nervous system causing strokes and seizures which currently can only be treated through neurosurgery. The disease arises through changes in the regulatory networks of endothelial cells that must be comprehensively understood to develop alternative, non-invasive pharmacological therapies. Here, we present the results of several unbiased small-molecule suppression screens in which we applied a total of 5,268 unique substances to CCM mutant worm, zebrafish, mouse, or human endothelial cells. We used a systems biology-based target prediction tool to integrate the results with the whole-transcriptome profile of zebrafish CCM2 mutants, revealing signaling pathways relevant to the disease and potential targets for small-molecule-based therapies. We found indirubin-3-monoxime to alleviate the lesion burden in murine preclinical models of CCM2 and CCM3 and suppress the loss-of-CCM phenotypes in human endothelial cells. Our multi-organism-based approach reveals new components of the CCM regulatory network and foreshadows novel small-molecule-based therapeutic applications for suppressing this devastating disease in patients. KW - angiogenesis KW - CCM KW - ERK5 KW - indirubin-3-monoxime KW - KLF2 Y1 - 2018 U6 - https://doi.org/10.15252/emmm.201809155 SN - 1757-4676 SN - 1757-4684 VL - 10 IS - 10 PB - Wiley CY - Hoboken ER -