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

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.

Automated summary

Studies have shown that CCM1- and CCM2-silenced endothelial cells expand in vitro and enter into a senescence-associated secretory phenotype (SASP), using this phenotype to invade the extracellular matrix and attract surrounding wild-type endothelial and immune cells. The SASP is driven by cytoskeletal, molecular, and transcriptomic disorders provoked by ROCK dysfunctions, suggesting that CCM2 and ROCK may be involved in controlling senescence and providing new insights into the role of cellular mechanics in the aging process. These in vitro findings help reconcile the dysregulated traits of CCM2-deficient endothelial cells into a unique fate, suggesting that SASP could link increased ROCK-dependent cell contractility with microenvironment remodeling and long-range chemo-attraction of endothelial and immune cells.