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- Title
Feedback between mechanosensitive signaling and active forces governs endothelial junction integrity.
- Authors
McEvoy, Eoin; Sneh, Tal; Moeendarbary, Emad; Javanmardi, Yousef; Efimova, Nadia; Yang, Changsong; Marino-Bravante, Gloria E.; Chen, Xingyu; Escribano, Jorge; Spill, Fabian; Garcia-Aznar, José Manuel; Weeraratna, Ashani T.; Svitkina, Tatyana M.; Kamm, Roger D.; Shenoy, Vivek B.
- 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. Gap formation in the vasculature underpins immune and tumour cell infiltration. Here the authors propose a chemo-mechanical model to analyse how feedback between mechanosensitive signalling, active cellular forces and adhesion governs the breakdown, recovery, and integrity of endothelial junctions.
- Subjects
VASCULAR endothelial cells; RHO GTPases; VASCULAR endothelium; ENDOTHELIUM; ION channels; ENDOTHELIAL cells; DRUG therapy
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-34701-y