Traffic Patterns of the Migrating Endothelium: How Force Transmission Regulates Vascular Malformation and Functional Shunting During Angiogenic Remodelling
Angiogenesis occurs in distinct phases: initial spouting is followed by remodelling in which endothelial cells (ECs) composing blood vessels rearrange by migrating against the direction of flow. Abnormal remodelling can result in vascular malformation. Such is the case in mutation of the Alk1 recept...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2022.840066/full |
| _version_ | 1811233495765221376 |
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| author | Lowell T. Edgar Hyojin Park Jessica R. Crawshaw James M. Osborne Anne Eichmann Anne Eichmann Anne Eichmann Miguel O. Bernabeu Miguel O. Bernabeu |
| author_facet | Lowell T. Edgar Hyojin Park Jessica R. Crawshaw James M. Osborne Anne Eichmann Anne Eichmann Anne Eichmann Miguel O. Bernabeu Miguel O. Bernabeu |
| author_sort | Lowell T. Edgar |
| collection | DOAJ |
| description | Angiogenesis occurs in distinct phases: initial spouting is followed by remodelling in which endothelial cells (ECs) composing blood vessels rearrange by migrating against the direction of flow. Abnormal remodelling can result in vascular malformation. Such is the case in mutation of the Alk1 receptor within the mouse retina which disrupts flow-migration coupling, creating mixed populations of ECs polarised with/against flow which aggregate into arteriovenous malformations (AVMs). The lack of live imaging options in vivo means that the collective EC dynamics that drive AVM and the consequences of mixed populations of polarity remain a mystery. Therefore, our goal is to present a novel agent-based model to provide theoretical insight into EC force transmission and collective dynamics during angiogenic remodelling. Force transmission between neighbouring agents consists of extrusive forces which maintain spacing and cohesive forces which maintain the collective. We performed migration simulations within uniformly polarised populations (against flow) and mixed polarity (with/against flow). Within uniformly polarised populations, extrusive forces stabilised the plexus by facilitating EC intercalation which ensures that cells remained evenly distributed. Excess cohesion disrupts intercalation, resulting in aggregations of cells and functional shunting. Excess cohesion between ECs prevents them from resolving diameter balances within the plexus, leading to prolonged flow reversals which exert a critical behaviour change within the system as they switch the direction of cell migration and traffic patterns at bifurcations. Introducing mixtures of cell polarity dramatically changed the role of extrusive forces within the system. At low extrusion, opposing ECs were able to move past each other; however, at high extrusion the pushing between cells resulted in migration speeds close to zero, forming traffic jams and disrupting migration. In our study, we produced vascular malformations and functional shunting with either excess cohesion between ECs or mixtures of cell polarity. At the centre of both these mechanisms are cell-cell adherens junctions, which are involved in flow sensing/polarity and must remodelling dynamically to allow rearrangements of cells during vascular patterning. Thus, our findings implicate junctional dysfunction as a new target in the treatment and prevention of vascular disease and AVMs. |
| first_indexed | 2024-04-12T11:20:59Z |
| format | Article |
| id | doaj.art-667fb91b26444d19ad97273fab9b4dae |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-04-12T11:20:59Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-667fb91b26444d19ad97273fab9b4dae2022-12-22T03:35:22ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2022-05-011010.3389/fcell.2022.840066840066Traffic Patterns of the Migrating Endothelium: How Force Transmission Regulates Vascular Malformation and Functional Shunting During Angiogenic RemodellingLowell T. Edgar0Hyojin Park1Jessica R. Crawshaw2James M. Osborne3Anne Eichmann4Anne Eichmann5Anne Eichmann6Miguel O. Bernabeu7Miguel O. Bernabeu8Centre for Medical Informatics, Usher Institute, The University of Edinburgh, Edinburgh, United KingdomCardiovascular Research Center Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, United StatesSchool of Mathematics and Statistics, University of Melbourne, Melbourne, VIC, AustraliaSchool of Mathematics and Statistics, University of Melbourne, Melbourne, VIC, AustraliaCardiovascular Research Center Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, United StatesYale University School of Medicine, Department of Cellular and Molecular Physiology, New Haven, CT, United StatesUniversité de Paris, PARCC, INSERM, Paris, FranceCentre for Medical Informatics, Usher Institute, The University of Edinburgh, Edinburgh, United KingdomThe Bayes Centre, The University of Edinburgh, Edinburgh, United KingdomAngiogenesis occurs in distinct phases: initial spouting is followed by remodelling in which endothelial cells (ECs) composing blood vessels rearrange by migrating against the direction of flow. Abnormal remodelling can result in vascular malformation. Such is the case in mutation of the Alk1 receptor within the mouse retina which disrupts flow-migration coupling, creating mixed populations of ECs polarised with/against flow which aggregate into arteriovenous malformations (AVMs). The lack of live imaging options in vivo means that the collective EC dynamics that drive AVM and the consequences of mixed populations of polarity remain a mystery. Therefore, our goal is to present a novel agent-based model to provide theoretical insight into EC force transmission and collective dynamics during angiogenic remodelling. Force transmission between neighbouring agents consists of extrusive forces which maintain spacing and cohesive forces which maintain the collective. We performed migration simulations within uniformly polarised populations (against flow) and mixed polarity (with/against flow). Within uniformly polarised populations, extrusive forces stabilised the plexus by facilitating EC intercalation which ensures that cells remained evenly distributed. Excess cohesion disrupts intercalation, resulting in aggregations of cells and functional shunting. Excess cohesion between ECs prevents them from resolving diameter balances within the plexus, leading to prolonged flow reversals which exert a critical behaviour change within the system as they switch the direction of cell migration and traffic patterns at bifurcations. Introducing mixtures of cell polarity dramatically changed the role of extrusive forces within the system. At low extrusion, opposing ECs were able to move past each other; however, at high extrusion the pushing between cells resulted in migration speeds close to zero, forming traffic jams and disrupting migration. In our study, we produced vascular malformations and functional shunting with either excess cohesion between ECs or mixtures of cell polarity. At the centre of both these mechanisms are cell-cell adherens junctions, which are involved in flow sensing/polarity and must remodelling dynamically to allow rearrangements of cells during vascular patterning. Thus, our findings implicate junctional dysfunction as a new target in the treatment and prevention of vascular disease and AVMs.https://www.frontiersin.org/articles/10.3389/fcell.2022.840066/fullangiogenesisangiogenic remodellingendothelial cellscollective migrationflow-migration couplingforce transmission |
| spellingShingle | Lowell T. Edgar Hyojin Park Jessica R. Crawshaw James M. Osborne Anne Eichmann Anne Eichmann Anne Eichmann Miguel O. Bernabeu Miguel O. Bernabeu Traffic Patterns of the Migrating Endothelium: How Force Transmission Regulates Vascular Malformation and Functional Shunting During Angiogenic Remodelling Frontiers in Cell and Developmental Biology angiogenesis angiogenic remodelling endothelial cells collective migration flow-migration coupling force transmission |
| title | Traffic Patterns of the Migrating Endothelium: How Force Transmission Regulates Vascular Malformation and Functional Shunting During Angiogenic Remodelling |
| title_full | Traffic Patterns of the Migrating Endothelium: How Force Transmission Regulates Vascular Malformation and Functional Shunting During Angiogenic Remodelling |
| title_fullStr | Traffic Patterns of the Migrating Endothelium: How Force Transmission Regulates Vascular Malformation and Functional Shunting During Angiogenic Remodelling |
| title_full_unstemmed | Traffic Patterns of the Migrating Endothelium: How Force Transmission Regulates Vascular Malformation and Functional Shunting During Angiogenic Remodelling |
| title_short | Traffic Patterns of the Migrating Endothelium: How Force Transmission Regulates Vascular Malformation and Functional Shunting During Angiogenic Remodelling |
| title_sort | traffic patterns of the migrating endothelium how force transmission regulates vascular malformation and functional shunting during angiogenic remodelling |
| topic | angiogenesis angiogenic remodelling endothelial cells collective migration flow-migration coupling force transmission |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2022.840066/full |
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