A mechanical modeling framework to study endothelial permeability

Pradeep Keshavanarayana*, Fabian Spill*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

The inner lining of blood vessels, the endothelium, is made up of endothelial cells. Vascular endothelial (VE)-cadherin protein forms a bond with VE-cadherin from neighboring cells to determine the size of gaps between the cells and thereby regulate the size of particles that can cross the endothelium. Chemical cues such as thrombin, along with mechanical properties of the cell and extracellular matrix are known to affect the permeability of endothelial cells. Abnormal permeability is found in patients suffering from diseases including cardiovascular diseases, cancer, and COVID-19. Even though some of the regulatory mechanisms affecting endothelial permeability are well studied, details of how several mechanical and chemical stimuli acting simultaneously affect endothelial permeability are not yet understood. In this article, we present a continuum-level mechanical modeling framework to study the highly dynamic nature of the VE-cadherin bonds. Taking inspiration from the catch-slip behavior that VE-cadherin complexes are known to exhibit, we model the VE-cadherin homophilic bond as cohesive contact with damage following a traction-separation law. We explicitly model the actin cytoskeleton and substrate to study their role in permeability. Our studies show that mechanochemical coupling is necessary to simulate the influence of the mechanical properties of the substrate on permeability. Simulations show that shear between cells is responsible for the variation in permeability between bicellular and tricellular junctions, explaining the phenotypic differences observed in experiments. An increase in the magnitude of traction force due to disturbed flow that endothelial cells experience results in increased permeability, and it is found that the effect is higher on stiffer extracellular matrix. Finally, we show that the cylindrical monolayer exhibits higher permeability than the planar monolayer under unconstrained cases. Thus, we present a contact mechanics-based mechanochemical model to investigate the variation in the permeability of endothelial monolayer due to multiple loads acting simultaneously.

Original languageEnglish
Pages (from-to)334-348
JournalBiophysical Journal
Volume123
Issue number3
Early online date1 Jan 2024
DOIs
Publication statusPublished - 6 Feb 2024

Bibliographical note

Funding Information:
We would like to acknowledge the funding from BBSRC grant BB/V002708/1 and UKRI Future Leaders Fellowship (MR/T043571/1). We would also like to thank Giovanni Guglielmi for discussions about using friendly colors in plots. We also thank the supercomputing facility at the University of Birmingham, BEAR, for constant support with computational requirements.

Publisher Copyright:
© 2023 Biophysical Society

ASJC Scopus subject areas

  • Biophysics

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