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  • Feedback between mechanosensitive signaling and active forces governs endothelial junction integrity.

Feedback between mechanosensitive signaling and active forces governs endothelial junction integrity.

Nature communications (2022-11-20)
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, Vivek B Shenoy
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
CK-666, ≥98% (HPLC), powder
Roche
Thrombin, from human plasma
Sigma-Aldrich
Arp2/3 Complex Inhibitor I, CK-666, Arp2/3 Complex Inhibitor I, CK-666, CAS 442633-00-3, is a cell-permeable selective inhibitor of actin assembly mediated by actin-related protein Arp2/3 complex (IC50 = 4 uM in human).