Letting go to hold on: loss of CCM2 disrupts endothelial force balance in cerebral cavernous malformations
- 1KULeuven
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.
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BibTeX
@misc{vorsselmans2026letting,
title = {{Letting go to hold on: loss of CCM2 disrupts endothelial force balance in cerebral cavernous malformations}},
author = {S. vorsselmans and S. Aytekin and C. Oddou and T. Manicom Ramsamy and E. Faurobert and S. Rocha},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.09.757835},
url = {https://www.biorxiv.org/content/10.64898/2026.10.09.757835v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Letting go to hold on: loss of CCM2 disrupts endothelial force balance in cerebral cavernous malformations
AU - S. vorsselmans
AU - S. Aytekin
AU - C. Oddou
AU - T. Manicom Ramsamy
AU - E. Faurobert
AU - S. Rocha
PY - 2026
DA - 2026/10/09
PB - bioRxiv
DO - 10.64898/2026.10.09.757835
UR - https://www.biorxiv.org/content/10.64898/2026.10.09.757835v1
AB - 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.
ER -