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, Vivek B. Shenoy*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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.

Original languageEnglish
Article number7089
Number of pages14
JournalNature Communications
Volume13
Issue number1
DOIs
Publication statusPublished - 19 Nov 2022

Bibliographical note

Funding Information:
This work was supported by NIH Awa rds U54CA261694 (R.D.K, V.B.S.) and R01GM095977 (T.M.S); NCI Awards R01CA232256 (A.T.W., V.B.S.) and R01CA207935 (A.T.W.); NSF CEMB Grant CMMI-154857 (V.B.S.); NSF Grants MRSEC/DMR-1720530 and DMS-1953572 (V.B.S.); Cancer Research UK Multidisciplinary Award C57744/A22057 (E.M.); Biotechnology and Biological Sciences Research Council Grant BB/V001418/1 (E.M., F.S.), Engineering and Physical Sciences Research Council EP/W009889/1 (E.M.). UKRI Future Leaders Fellowship MR/T043571/1 (F.S.); Spanish Ministry of Science, Innovation and Universities RTI2018-094494-B-C21 (J.M.G.A.); NIBIB Awards R01EB017753 and R01EB030876 (V.B.S.)

Publisher Copyright:
© 2022, The Author(s).

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology
  • General
  • General Physics and Astronomy

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