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 - Haack, Timm A1 - Abdelilah-Seyfried, Salim T1 - The force within: endocardial development, mechanotransduction and signalling during cardiac morphogenesis JF - Development : Company of Biologists N2 - Endocardial cells are cardiac endothelial cells that line the interior of the heart tube. Historically, their contribution to cardiac development has mainly been considered from a morphological perspective. However, recent studies have begun to define novel instructive roles of the endocardium, as a sensor and signal transducer of biophysical forces induced by blood flow, and as an angiocrine signalling centre that is involved in myocardial cellular morphogenesis, regeneration and reprogramming. In this Review, we discuss how the endocardium develops, how endocardial-myocardial interactions influence the developing embryonic heart, and how the dysregulation of blood flowresponsive endocardial signalling can result in pathophysiological changes. KW - Endocardium KW - Cardiac development KW - Hemodynamics KW - Bmp KW - Kruppel-like factor 2 KW - Vegf KW - Mechanotransduction KW - Zebrafish KW - Mouse Y1 - 2016 U6 - https://doi.org/10.1242/dev.131425 SN - 0950-1991 SN - 1477-9129 VL - 143 SP - 373 EP - 386 PB - Company of Biologists Limited CY - Cambridge ER - TY - JOUR A1 - Franco-Obregon, Alfredo A1 - Cambria, Elena A1 - Greutert, Helen A1 - Wernas, Timon A1 - Hitzl, Wolfgang A1 - Egli, Marcel A1 - Sekiguchi, Miho A1 - Boos, Norbert A1 - Hausmann, Oliver A1 - Ferguson, Stephen J. A1 - Kobayashi, Hiroshi A1 - Würtz-Kozak, Karin T1 - TRPC6 in simulated microgravity of intervertebral disc cells JF - European Spine Journal N2 - Purpose Prolonged bed rest and microgravity in space cause intervertebral disc (IVD) degeneration. However, the underlying molecular mechanisms are not completely understood. Transient receptor potential canonical (TRPC) channels are implicated in mechanosensing of several tissues, but are poorly explored in IVDs. Methods Primary human IVD cells from surgical biopsies composed of both annulus fibrosus and nucleus pulposus (passage 1-2) were exposed to simulated microgravity and to the TRPC channel inhibitor SKF-96365 (SKF) for up to 5days. Proliferative capacity, cell cycle distribution, senescence and TRPC channel expression were analyzed. Results Both simulated microgravity and TRPC channel antagonism reduced the proliferative capacity of IVD cells and induced senescence. While significant changes in cell cycle distributions (reduction in G1 and accumulation in G2/M) were observed upon SKF treatment, the effect was small upon 3days of simulated microgravity. Finally, downregulation of TRPC6 was shown under simulated microgravity. Conclusions Simulated microgravity and TRPC channel inhibition both led to reduced proliferation and increased senescence. Furthermore, simulated microgravity reduced TRPC6 expression. IVD cell senescence and mechanotransduction may hence potentially be regulated by TRPC6 expression. This study thus reveals promising targets for future studies. KW - Intervertebral disc KW - Simulated microgravity KW - Senescence KW - TRP channels KW - Mechanotransduction KW - Gene expression Y1 - 2018 U6 - https://doi.org/10.1007/s00586-018-5688-8 SN - 0940-6719 SN - 1432-0932 VL - 27 IS - 10 SP - 2621 EP - 2630 PB - Springer CY - New York ER -