TY - JOUR
T1 - On the preservation of vessel bifurcations during flow-mediated angiogenic remodelling
AU - Edgar, Lowell T.
AU - Franco, Cláudio A.
AU - Gerhardt, Holger
AU - Bernabeu, Miguel O.
N1 - Funding Information:
EPSRC(EP/R029598/1,EP/R021600/1).C.A.Fwas supportedbyEuropeanResearchCouncilstarting grant(679368),theFundac ¸ãoparaaCiênciaea Tecnologiafunding(grants:PTDC/MED-PAT/ 31639/2017;PTDC/BIA-CEL/32180/2017; CEECIND/04251/2017).C.A.F.andM.O.Bare supportedbyagrantfromtheEuropeanUnion’s Horizon2020researchandinnovationprogramme undergrantagreementNo801423.Thefunders hadnoroleinstudydesign,datacollectionand analysis,decisiontopublish,orpreparationofthe manuscript.
Funding Information:
L.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 Fundacão 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.
Publisher Copyright:
© 2021 Edgar et al.
PY - 2021/2/4
Y1 - 2021/2/4
N2 - 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 flowbased 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.
AB - 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 flowbased 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.
UR - http://www.scopus.com/inward/record.url?scp=85101307056&partnerID=8YFLogxK
U2 - 10.1371/JOURNAL.PCBI.1007715
DO - 10.1371/JOURNAL.PCBI.1007715
M3 - Article
C2 - 33539345
AN - SCOPUS:85101307056
SN - 1553-734X
VL - 17
JO - PLoS Computational Biology
JF - PLoS Computational Biology
IS - 2
M1 - e1007715
ER -