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

Abstract

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.