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CCM2-deficient endothelial cells undergo a ROCK-dependent reprogramming into senescence-associated secretory phenotype

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Abstract

Cerebral cavernous malformation (CCM) is a cerebrovascular disease in which stacks of dilated haemorrhagic capillaries form focally in the brain. Whether and how defective mechanotransduction, cellular mosaicism and inflammation interplay to sustain the progression of CCM disease is unknown. Here, we reveal that CCM1- and CCM2-silenced endothelial cells expanded in vitro enter into senescence-associated secretory phenotype (SASP) that they use to invade the extracellular matrix and attract surrounding wild-type endothelial and immune cells. Further, we demonstrate that this SASP is driven by the cytoskeletal, molecular and transcriptomic disorders provoked by ROCK dysfunctions. By this, we propose that CCM2 and ROCK could be parts of a scaffold controlling senescence, bringing new insights into the emerging field of the control of ageing by cellular mechanics. These in vitro findings reconcile the known dysregulated traits of CCM2-deficient endothelial cells into a unique endothelial fate. Based on these in vitro results, we propose that a SASP could link the increased ROCK-dependent cell contractility in CCM2-deficient endothelial cells with microenvironment remodelling and long-range chemo-attraction of endothelial and immune cells.

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Data availability

The raw data (FastQ files) and processed data (count files) are deposited in the Gene Expression Omnibus database. All data supporting the findings of this study are available from the corresponding author on reasonable request.

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Acknowledgements

Most of the computations presented in this paper were performed using the CIMENT/GRICAD infrastructure (https://gricad.univ-grenoble-alpes.fr). The authors acknowledge the EpiMed core facility (http://epimed.univ-grenoble-alpes.fr) for their support and assistance in this work. This study was supported by the ANR (ANR-17-CE13-022), the Fondation pour la Recherche Médicale FRM (DEQ20170336702), the International Emerging Action CNRS, the association Espoir contre le Cancer Isère, the FWO project G087018N, infrastructure Grant I009718N, Hercules Foundation (G0H6316N), the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007–2013)/ERC Grant Agreement No. 308223). PhD fellowship grants were supported by ANR and FRM to D.R.V. and FWO (1S68818N) to A.S. We would like to thank Claudia Röedel, Béatrice Eymin and Gwénola Boulday for sharing ideas and reagents; Salim Seyfried for critical reading of the manuscript; and Christiane Oddou for excellent technical assistance.

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  1. Corinne Albiges-Rizo, Hans Van Oosterwyck and Eva Faurobert are co-last authors.

Authors and Affiliations

  1. Institute for Advanced Biosciences, University Grenoble Alpes, INSERM U1209, CNRS UMR5309, site santé, Allée des Alpes, 38042, Grenoble, France

    Daphné Raphaëlle Vannier, Florent Chuffart, Emmanuelle Planus, Sandra Manet, Paul Rivier, Olivier Destaing, Corinne Albiges-Rizo & Eva Faurobert

  2. Biomechanics Section (BMe), Department of Mechanical Engineering, KU Leuven, Leuven, Belgium

    Apeksha Shapeti & Hans Van Oosterwyck

  3. Division Prometheus, Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium

    Apeksha Shapeti & Hans Van Oosterwyck

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  1. Daphné Raphaëlle Vannier
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Contributions

DRV, AS, HVO, EF conceived the project and designed experiments; DRV, AS, SM, EP, EF performed experiments; FC, DRV, EF analysed the bioinformatical data; OD contributed to scientific discussion; PR provided reagents; CAR, EF and HVO provided funding; EF wrote the manuscript which has been revised by all authors.

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Correspondence to Eva Faurobert.

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Sandra Manet—deceased

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Vannier, D.R., Shapeti, A., Chuffart, F. et al. CCM2-deficient endothelial cells undergo a ROCK-dependent reprogramming into senescence-associated secretory phenotype. Angiogenesis 24, 843–860 (2021). https://doi.org/10.1007/s10456-021-09809-2

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