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

Autor: McEvoy E; Department of Materials Science and Engineering, University of Pennsylvania, Philadelphia, PA, 19104, USA.; Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA, 19104, USA.; Biomedical Engineering, University of Galway, Galway, H91 HX31, Ireland., Sneh T; Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA, 19104, USA.; Center for Molecular Design and Biomimetics, The Biodesign Institute, Arizona State University, Tempe, AZ, 85287, USA., Moeendarbary E; Department of Mechanical Engineering, University College London, London, WC1E 7JE, UK.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA., Javanmardi Y; Department of Mechanical Engineering, University College London, London, WC1E 7JE, UK., Efimova N; Department of Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA., Yang C; Department of Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA., Marino-Bravante GE; Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA.; Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA., Chen X; Department of Materials Science and Engineering, University of Pennsylvania, Philadelphia, PA, 19104, USA.; Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA, 19104, USA., Escribano J; Department of Mechanical Engineering, University of Zaragoza, Zaragoza, Spain., Spill F; School of Mathematics, University of Birmingham, Birmingham, B15 2TT, United Kingdom., Garcia-Aznar JM; Department of Mechanical Engineering, University of Zaragoza, Zaragoza, Spain., Weeraratna AT; Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA.; Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA., Svitkina TM; Department of Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA., Kamm RD; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA., Shenoy VB; Department of Materials Science and Engineering, University of Pennsylvania, Philadelphia, PA, 19104, USA. vshenoy@seas.upenn.edu.; Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA, 19104, USA. vshenoy@seas.upenn.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Nov 19; Vol. 13 (1), pp. 7089. Date of Electronic Publication: 2022 Nov 19.
DOI: 10.1038/s41467-022-34701-y
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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