Feedback between mechanosensitive signaling and active forces governs endothelial junction integrity

McEvoy, E. ; Sneh, T. ; Moeendarbary, E. ; Javanmardi, Y. ; Efimova, N. ; Yang, C. ; Marino-Bravante, G. E. ; Chen, X. ; Escribano, J. ; Spill, F. ; Garcia-Aznar, J. M. (Universidad de Zaragoza) ; Weeraratna, A. T. ; Svitkina, T. M. ; Kamm, R. D. ; Shenoy, V. B.

Resumen: 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.

Idioma: Inglés

DOI: 10.1038/s41467-022-34701-y

Año: 2022

Publicado en: Nature communications 13 (2022), 7089[14 pp.]
ISSN: 2041-1723

Factor impacto JCR: 16.6 (2022)

Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 6 / 73 = 0.082 (2022) - Q1 - T1

Factor impacto CITESCORE: 24.9 - Physics and Astronomy (Q1) - General (Q1) - Chemistry (Q1) - Biochemistry, Genetics and Molecular Biology (Q1)

Factor impacto SCIMAGO: 5.116 - Biochemistry, Genetics and Molecular Biology (miscellaneous) (Q1) - Physics and Astronomy (miscellaneous) (Q1) - Chemistry (miscellaneous) (Q1)

Financiación: info:eu-repo/grantAgreement/ES/MICINN/RTI2018-094494-B-C21

Tipo y forma: Artículo (Versión definitiva)

Área (Departamento): Área Mec.Med.Cont. y Teor.Est. (Dpto. Ingeniería Mecánica)