Manicom Ramsamy, T. | bioRxiv Science

bioRxiv2026

Letting go to hold on: loss of CCM2 disrupts endothelial force balance in cerebral cavernous malformations

Cerebral cavernous malformations (CCM) are vascular lesions characterized by impaired endothelial integrity and altered cell-cell and cell-matrix interactions. While endothelial contractility and tractions have been implicated in CCM, how these forces are transmitted and coordinated across adhesion systems remains unknown. Here, we combined genetically encoded FRET-based molecular tension sensors of vinculin and VE-cadherin with quantitative analysis of adhesion organization to dissect this force balance in CCM2-deficient endothelial monolayers. We found that CCM2 loss redistributes molecular forces, partially through ROCK-dependent contractility, across endothelial adhesions, shifting mechanical engagement from cell-cell junctions toward the cell-matrix interface. Matrix stiffness further amplifies this imbalance, as healthy endothelial cells maintain the balance between cell-cell and cell-matrix adhesions by reinforcing both in response to stiffening, whereas CCM2-deficient cells preferentially reinforce the cell-matrix interface. These findings suggest that CCM-associated matrix remodeling could reinforce an already altered mechanical state, establishing a potential feed-forward interaction between endothelial force transmission and the extracellular environment. More broadly, our results identify the CCM complex as a molecular hub controlling force balance in response to the cell mechanical environment and establish a combined tension sensing and morphology-based imaging platform for studying adhesion mechanobiology.

biophysics↗

bioRxiv2026

Endothelial gain of PIEZO/TRPV mechanosensors drives cavernous malformations

Vascular disease often begins as a failure to read mechanical force. Cerebral cavernous malformations (CCMs) are leaky, brain-invading capillary clusters that cause stroke and seizures and arise from endothelial loss of the CCM complex. They form exclusively in low-flow vessels but existing models cannot explain this selectivity. We previously established that CCM-mutant endothelium inverts its adhesive balance, weakening cell-cell junctions while building matrix-degrading adhesions. The mechanosensors imposing this switch are unknown. Here we show that the mechanosensitive Ca2+ channels PIEZO1, TRPV2 and TRPV4 are overexpressed in the endothelium of CCM lesions in a 42-patient cohort, and that lesion volume scales with their expression level. Mechanistically, PIEZO1 partners with TRPV4 to destabilise cell-cell junctions and with TRPV2 to reinforce cell-matrix adhesions; silencing TRPV4 restores junctional integrity and abolishes KLF4 induction, whereas silencing TRPV2 or inhibition with tranilast abolishes matrix degradation and invasion. In vivo, trpv4 knockdown or inhibition with GSK2798745 restores atrioventricular canal morphogenesis in ccm2-mutant zebrafish. Gain of mechanosensory channel function is thus a causal step in CCM pathogenesis, upstream of the KLF program. Combined therapeutic targeting of TRPV2 and TRPV4 with inhibitors validated in humans offers a route to therapy.

cell biology↗