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.

Small GTPases all over invadosomes.

Cell invasion is associated with numerous patho-physiologic states including cell development and metastatic dissemination. This process couples the activation of cell motility with the capacity to degrade the extracellular matrix, thereby permitting cells to pass through basal membranes. Invasion is sustained by the actions of invadosomes, an ensemble of subcellular structures with high functional homology.

Cross-talk between the calcium channel TRPV4 and reactive oxygen species interlocks adhesive and degradative functions of invadosomes.

Invadosomes support cell invasion by coupling both acto-adhesive and extracellular matrix degradative functions, which are apparently antagonistic. β1-integrin dynamics regulate this coupling, but the actual sensing mechanism and effectors involved have not yet been elucidated. Using genetic and reverse genetic approaches combined with biochemical and imaging techniques, we now show that the calcium channel TRPV4 colocalizes with β1-integrins at the invadosome periphery and regulates its activation and the coupling of acto-adhesive and degradative functions.