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On the preservation of vessel bifurcations during flow-mediated angiogenic remodelling

2021Artigo científico Acesso aberto
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dc.contributor.authorEdgar, Lowell T.
dc.contributor.authorFranco, Claudio
dc.contributor.authorGerhardt, Holger
dc.contributor.authorBernabeu, Miguel O.
dc.date.accessioned2021-07-29T13:12:24Z
dc.date.available2021-07-29T13:12:24Z
dc.date.issued2021
dc.descriptionCopyright: © 2021 Edgar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.pt_PT
dc.description.abstractDuring 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.pt_PT
dc.description.sponsorshipL.T.E, C.A.F, H.G., and M.O.B. would like to graciously acknowledge our funding as part of a Foundation Leducq Transatlantic Network of Excellence (17 CVD 03, https://www.mdc-berlin.de/leducq-attract). M.O.B is supported by grants from EPSRC (EP/R029598/1, EP/R021600/1). C.A.F was supported by European Research Council starting grant (679368), the Fundação para a Ciência e a Tecnologia funding (grants: PTDC/MED-PAT/31639/2017; PTDC/BIA-CEL/32180/2017; CEECIND/04251/2017). C.A.F. and M.O.B are supported by a grant from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 801423. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationPLoS Comput Biol 17(2): e1007715.pt_PT
dc.identifier.doi10.1371/journal.pcbi.1007715pt_PT
dc.identifier.eissn1553-7358
dc.identifier.issn1553-734X
dc.identifier.urihttp://hdl.handle.net/10451/49207
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherPLOSpt_PT
dc.relationPRINCIPLES OF AXIAL POLARITY-DRIVEN VASCULAR PATTERNING
dc.relationDeregulated Endothelial Blood Flow Response as a cause of Diabetic Retinopathy
dc.relationIdentify the mechanisms of endothelial tip cell invasive behavior in order to inhibit physiological and pathological sprouting angiogenesis
dc.relationNot Available
dc.relationBuilding a 3D innervated and irrigated muscle on a chip.
dc.relation.publisherversionhttps://journals.plos.org/ploscompbiol/pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.titleOn the preservation of vessel bifurcations during flow-mediated angiogenic remodellingpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitlePRINCIPLES OF AXIAL POLARITY-DRIVEN VASCULAR PATTERNING
oaire.awardTitleDeregulated Endothelial Blood Flow Response as a cause of Diabetic Retinopathy
oaire.awardTitleIdentify the mechanisms of endothelial tip cell invasive behavior in order to inhibit physiological and pathological sprouting angiogenesis
oaire.awardTitleNot Available
oaire.awardTitleBuilding a 3D innervated and irrigated muscle on a chip.
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/679368/EU
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FMED-PAT%2F31639%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FBIA-CEL%2F32180%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/CEEC IND 2017/CEECIND%2F04251%2F2017%2FCP1396%2FCT0010/PT
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/801423/EU
oaire.citation.issue2pt_PT
oaire.citation.titlePLOS Computational Biologypt_PT
oaire.citation.volume17pt_PT
oaire.fundingStreamH2020
oaire.fundingStream3599-PPCDT
oaire.fundingStream3599-PPCDT
oaire.fundingStreamCEEC IND 2017
oaire.fundingStreamH2020
person.familyNameFranco
person.givenNameClaudio
person.identifierD-8117-2015
person.identifier.ciencia-idF012-B7D6-AE72
person.identifier.orcid0000-0002-2861-3883
person.identifier.scopus-author-id24280736600
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.nameEuropean Commission
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameEuropean Commission
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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relation.isAuthorOfPublication.latestForDiscovery633fb0a6-1f81-4d35-98ca-b4cfd838d81e
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