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On the preservation of vessel bifurcations during flow-mediated angiogenic remodelling
During developmental angiogenesis, endothelial cells respond to shear stress by migrating and remodelling the initially hyperbranched plexus, removing certain vessels whilst maintaining others. In this study, we argue that the key regulator of vessel preservation is cell decision behaviour at bifurc...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909651/ https://www.ncbi.nlm.nih.gov/pubmed/33539345 http://dx.doi.org/10.1371/journal.pcbi.1007715 |
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author | Edgar, Lowell T. Franco, Claudio A. Gerhardt, Holger Bernabeu, Miguel O. |
author_facet | Edgar, Lowell T. Franco, Claudio A. Gerhardt, Holger Bernabeu, Miguel O. |
author_sort | Edgar, Lowell T. |
collection | PubMed |
description | During developmental angiogenesis, endothelial cells respond to shear stress by migrating and remodelling the initially hyperbranched plexus, removing certain vessels whilst maintaining others. In this study, we argue that the key regulator of vessel preservation is cell decision behaviour at bifurcations. At flow-convergent bifurcations where migration paths diverge, cells must finely tune migration along both possible paths if the bifurcation is to persist. Experiments have demonstrated that disrupting the cells’ ability to sense shear or the junction forces transmitted between cells impacts the preservation of bifurcations during the remodelling process. However, how these migratory cues integrate during cell decision making remains poorly understood. Therefore, we present the first agent-based model of endothelial cell flow-mediated migration suitable for interrogating the mechanisms behind bifurcation stability. The model simulates flow in a bifurcated vessel network composed of agents representing endothelial cells arranged into a lumen which migrate against flow. Upon approaching a bifurcation where more than one migration path exists, agents refer to a stochastic bifurcation rule which models the decision cells make as a combination of flow-based and collective-based migratory cues. With this rule, cells favour branches with relatively larger shear stress or cell number. We found that cells must integrate both cues nearly equally to maximise bifurcation stability. In simulations with stable bifurcations, we found competitive oscillations between flow and collective cues, and simulations that lost the bifurcation were unable to maintain these oscillations. The competition between these two cues is haemodynamic in origin, and demonstrates that a natural defence against bifurcation loss during remodelling exists: as vessel lumens narrow due to cell efflux, resistance to flow and shear stress increases, attracting new cells to enter and rescue the vessel from regression. Our work provides theoretical insight into the role of junction force transmission has in stabilising vasculature during remodelling and as an emergent mechanism to avoid functional shunting. |
format | Online Article Text |
id | pubmed-7909651 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-79096512021-03-05 On the preservation of vessel bifurcations during flow-mediated angiogenic remodelling Edgar, Lowell T. Franco, Claudio A. Gerhardt, Holger Bernabeu, Miguel O. PLoS Comput Biol Research Article During developmental angiogenesis, endothelial cells respond to shear stress by migrating and remodelling the initially hyperbranched plexus, removing certain vessels whilst maintaining others. In this study, we argue that the key regulator of vessel preservation is cell decision behaviour at bifurcations. At flow-convergent bifurcations where migration paths diverge, cells must finely tune migration along both possible paths if the bifurcation is to persist. Experiments have demonstrated that disrupting the cells’ ability to sense shear or the junction forces transmitted between cells impacts the preservation of bifurcations during the remodelling process. However, how these migratory cues integrate during cell decision making remains poorly understood. Therefore, we present the first agent-based model of endothelial cell flow-mediated migration suitable for interrogating the mechanisms behind bifurcation stability. The model simulates flow in a bifurcated vessel network composed of agents representing endothelial cells arranged into a lumen which migrate against flow. Upon approaching a bifurcation where more than one migration path exists, agents refer to a stochastic bifurcation rule which models the decision cells make as a combination of flow-based and collective-based migratory cues. With this rule, cells favour branches with relatively larger shear stress or cell number. We found that cells must integrate both cues nearly equally to maximise bifurcation stability. In simulations with stable bifurcations, we found competitive oscillations between flow and collective cues, and simulations that lost the bifurcation were unable to maintain these oscillations. The competition between these two cues is haemodynamic in origin, and demonstrates that a natural defence against bifurcation loss during remodelling exists: as vessel lumens narrow due to cell efflux, resistance to flow and shear stress increases, attracting new cells to enter and rescue the vessel from regression. Our work provides theoretical insight into the role of junction force transmission has in stabilising vasculature during remodelling and as an emergent mechanism to avoid functional shunting. Public Library of Science 2021-02-04 /pmc/articles/PMC7909651/ /pubmed/33539345 http://dx.doi.org/10.1371/journal.pcbi.1007715 Text en © 2021 Edgar et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Edgar, Lowell T. Franco, Claudio A. Gerhardt, Holger Bernabeu, Miguel O. On the preservation of vessel bifurcations during flow-mediated angiogenic remodelling |
title | On the preservation of vessel bifurcations during flow-mediated angiogenic remodelling |
title_full | On the preservation of vessel bifurcations during flow-mediated angiogenic remodelling |
title_fullStr | On the preservation of vessel bifurcations during flow-mediated angiogenic remodelling |
title_full_unstemmed | On the preservation of vessel bifurcations during flow-mediated angiogenic remodelling |
title_short | On the preservation of vessel bifurcations during flow-mediated angiogenic remodelling |
title_sort | on the preservation of vessel bifurcations during flow-mediated angiogenic remodelling |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909651/ https://www.ncbi.nlm.nih.gov/pubmed/33539345 http://dx.doi.org/10.1371/journal.pcbi.1007715 |
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