Integrin β1-Talin1 at focal adhesions underpin uncontrolled endothelial cell enlargement in live cerebral cavernous malformation vasculature

Keyser, M. S.; Yordanov, T. E.; da Silva, J. A.; Chau, T. C.; Morris, E. K.; Paterson, S.; Bower, N.; Koltowska, K.; Baillie, G. J.; Simons, C.; Parton, R. G.; Smith, K. A.; Hogan, B. M.; Lagendijk, A. K.

doi:10.1101/2025.11.25.688491

bioRxiv · 10.1101/2025.11.25.688491

Integrin β1-Talin1 at focal adhesions underpin uncontrolled endothelial cell enlargement in live cerebral cavernous malformation vasculature

Keyser, M. S.·Yordanov, T. E.·da Silva, J. A.·Chau, T. C.·Morris, E. K.·Paterson, S.·Bower, N.·Koltowska, K.·Baillie, G. J.·Simons, C.·Parton, R. G.·Smith, K. A.·Hogan, B. M.·Lagendijk, A. K.

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Abstract

Cerebral cavernous malformations (CCMs) are vascular anomalies caused by loss of CCM gene function and consequent hyperactivation of MEKK3-KLF2/4 signaling in endothelial cells. Excess integrin {beta}1 activity has been associated with lesion growth, yet the precise mechanistic and biomechanical roles of the integrin-KLF2/4 hierarchy in CCM cellular pathogenesis are not fully understood. Using live imaging of endothelial Vinculin in Ccm1-deficient zebrafish, we demonstrate excessive, mechanically active focal adhesions in an in vivo model of CCM pathology. We validate this in CCM1-deficient endothelial cells and show a redistribution of mechanical tension from cell-cell junctions to focal adhesions. Genetic deletion of Talin1 to decouple focal adhesions from the cell cortex and inhibit integrin {beta}1 signaling demonstrates the integrin {beta}1-Talin1 complex is essential for vascular malformations in ccm1 mutants by driving endothelial cell enlargement. We show integrin {beta}1-Talin1 act independent or downstream of KLF2/4, rather than upstream as previously suggested. Thus, we reposition the role of integrin {beta}1-Talin1 in CCM pathogenesis, demonstrating an essential function in driving cell enlargement, which underpins lesion growth.

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Keyser, M. S., Yordanov, T. E., da Silva, J. A., Chau, T. C., Morris, E. K., Paterson, S., Bower, N., Koltowska, K., Baillie, G. J., Simons, C., Parton, R. G., Smith, K. A., Hogan, B. M., Lagendijk, A. K.. 2025-11-27. Integrin β1-Talin1 at focal adhesions underpin uncontrolled endothelial cell enlargement in live cerebral cavernous malformation vasculature. https://doi.org/10.1101/2025.11.25.688491

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