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

Abstract

During developmental angiogenesis, endothelial cells respond to shear stress by migrating and remodelling the initially hyperbranched plexus, removing certain vessels whilst maintaining others. 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 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.Author Summary: When new blood vessels are created, the endothelial cells that make up these vessels migrate and rearrange in response to blood flow to remodel and optimise the vessel network. An essential part of this process is maintaining the branched structure of the network; however, it is unclear what cues cells consider at regions were vessels branch (i.e., bifurcations). In this research, we present a computer model of cell migration to interrogate the process of preserving bifurcations during remodelling. In this model, cells at bifurcations are influenced by both flow and force transmitted from neighbouring cells. We found that both cues (flow-based and collective-based) must be considered equally in order to preserve branching in the vessel network. In simulations with stable bifurcations, we demonstrated that these cues oscillate: a strong signal in one was accompanied by a weak signal in the other. Furthermore, we found that these cues naturally compete with each other due to the coupling between blood flow and the size of the blood vessels, i.e. larger vessels with more cells produce less flow signals and vice versa. Our research provides insight into how forces transmitted between neighbouring cells stabilises and preserves branching during remodelling, as well as implicates the disruption of this force transmission as a potential mechanism when remodelling goes wrong as in the case of vascular malformation.