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PLoS Comput Biol. 2019 May 2;15(5):e1006395. doi: 10.1371/journal.pcbi.1006395. eCollection 2019 May.

Balance of mechanical forces drives endothelial gap formation and may facilitate cancer and immune-cell extravasation.

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Department of Mechanical Engineering, University of Zaragoza, Zaragoza, Spain.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
Department of Bioengineering, Stanford University, Stanford, California, United States of America.
Department of Mechanical Engineering, University College London, London, United Kingdom.
Department of Materials Science and Engineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
BioSystems and Micromechanics (BioSyM), Singapore-MIT Alliance for Research and Technology, Singapore, Singapore.
School of Mathematics, University of Birmingham, Birmingham, United Kingdom.


The formation of gaps in the endothelium is a crucial process underlying both cancer and immune cell extravasation, contributing to the functioning of the immune system during infection, the unfavorable development of chronic inflammation and tumor metastasis. Here, we present a stochastic-mechanical multiscale model of an endothelial cell monolayer and show that the dynamic nature of the endothelium leads to spontaneous gap formation, even without intervention from the transmigrating cells. These gaps preferentially appear at the vertices between three endothelial cells, as opposed to the border between two cells. We quantify the frequency and lifetime of these gaps, and validate our predictions experimentally. Interestingly, we find experimentally that cancer cells also preferentially extravasate at vertices, even when they first arrest on borders. This suggests that extravasating cells, rather than initially signaling to the endothelium, might exploit the autonomously forming gaps in the endothelium to initiate transmigration.

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