Feedback between mechanosensitive signaling and active forces governs endothelial junction integrity

Eoin McEvoy, Tal Sneh, Emad Moeendarbary, Yousef Javanmardi, Nadia Efimova, Changsong Yang, Gloria E. Marino-Bravante, Xingyu Chen, Jorge Escribano, Fabian Spill, José Manuel Garcia-Aznar, Ashani T. Weeraratna, Tatyana M. Svitkina, Roger D. Kamm and Vivek B. Shenoy ()
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Eoin McEvoy: University of Pennsylvania
Tal Sneh: University of Pennsylvania
Emad Moeendarbary: University College London
Yousef Javanmardi: University College London
Nadia Efimova: University of Pennsylvania
Changsong Yang: University of Pennsylvania
Gloria E. Marino-Bravante: Johns Hopkins Bloomberg School of Public Health
Xingyu Chen: University of Pennsylvania
Jorge Escribano: University of Zaragoza
Fabian Spill: University of Birmingham
José Manuel Garcia-Aznar: University of Zaragoza
Ashani T. Weeraratna: Johns Hopkins Bloomberg School of Public Health
Tatyana M. Svitkina: University of Pennsylvania
Roger D. Kamm: Massachusetts Institute of Technology
Vivek B. Shenoy: University of Pennsylvania

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract The formation and recovery of gaps in the vascular endothelium governs a wide range of physiological and pathological phenomena, from angiogenesis to tumor cell extravasation. However, the interplay between the mechanical and signaling processes that drive dynamic behavior in vascular endothelial cells is not well understood. In this study, we propose a chemo-mechanical model to investigate the regulation of endothelial junctions as dependent on the feedback between actomyosin contractility, VE-cadherin bond turnover, and actin polymerization, which mediate the forces exerted on the cell-cell interface. Simulations reveal that active cell tension can stabilize cadherin bonds, but excessive RhoA signaling can drive bond dissociation and junction failure. While actin polymerization aids gap closure, high levels of Rac1 can induce junction weakening. Combining the modeling framework with experiments, our model predicts the influence of pharmacological treatments on the junction state and identifies that a critical balance between RhoA and Rac1 expression is required to maintain junction stability. Our proposed framework can help guide the development of therapeutics that target the Rho family of GTPases and downstream active mechanical processes.

Date: 2022
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DOI: 10.1038/s41467-022-34701-y

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