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Feedback between mechanosensitive signaling and active forces governs endothelial junction integrity

Author

Listed:
  • Eoin McEvoy

    (University of Pennsylvania
    University of Pennsylvania
    University of Galway)

  • Tal Sneh

    (University of Pennsylvania
    Arizona State University)

  • Emad Moeendarbary

    (University College London
    Massachusetts Institute of Technology)

  • 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
    Johns Hopkins School of Medicine)

  • Xingyu Chen

    (University of Pennsylvania
    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
    Johns Hopkins School of Medicine)

  • Tatyana M. Svitkina

    (University of Pennsylvania)

  • Roger D. Kamm

    (Massachusetts Institute of Technology)

  • Vivek B. Shenoy

    (University of Pennsylvania
    University of Pennsylvania)

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.

Suggested Citation

  • 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 & , 2022. "Feedback between mechanosensitive signaling and active forces governs endothelial junction integrity," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34701-y
    DOI: 10.1038/s41467-022-34701-y
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    References listed on IDEAS

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    1. Amalia Hadjitheodorou & George R. R. Bell & Felix Ellett & Shashank Shastry & Daniel Irimia & Sean R. Collins & Julie A. Theriot, 2021. "Directional reorientation of migrating neutrophils is limited by suppression of receptor input signaling at the cell rear through myosin II activity," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    2. Kristine Manibog & Hui Li & Sabyasachi Rakshit & Sanjeevi Sivasankar, 2014. "Resolving the molecular mechanism of cadherin catch bond formation," Nature Communications, Nature, vol. 5(1), pages 1-11, September.
    3. Girish R. Kale & Xingbo Yang & Jean-Marc Philippe & Madhav Mani & Pierre-François Lenne & Thomas Lecuit, 2018. "Distinct contributions of tensile and shear stress on E-cadherin levels during morphogenesis," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    4. Eoin McEvoy & Yu Long Han & Ming Guo & Vivek B. Shenoy, 2020. "Gap junctions amplify spatial variations in cell volume in proliferating tumor spheroids," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
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