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AbstractWe introduce a hybrid two-dimensional multiscale model of angiogenesis, the process by which endothelial cells (ECs) migrate from a pre-existing vascular bed in response to local environmental cues and cell-cell interactions, to create a new vascular network. Recent experimental studies have highlighted a central role of cell rearrangements in the formation of angiogenic networks. Our model accounts for this phenomenon via the heterogeneous response of ECs to their microenvironment. These cell rearrangements, in turn, dynamically remodel the local environment. The model reproduces characteristic features of angiogenic sprouting that include branching, chemotactic sensitivity, the brush border effect, and cell mixing. These properties, rather than being hardwired into the model, emerge naturally from the gene expression patterns of individual cells. After calibrating and validating our model against experimental data, we use it to predict how the structure of the vascular network changes as the baseline gene expression levels of the VEGF-Delta-Notch pathway, and the composition of the extracellular environment, vary. In order to investigate the impact of cell rearrangements on the vascular network structure, we introduce the mixing measure, a scalar metric that quantifies cell mixing as the vascular network grows. We calculate the mixing measure for the simulated vascular networks generated by ECs of different lineages (wild type cells and mutant cells with impaired expression of a specific receptor). Our results show that the time evolution of the mixing measure is directly correlated to the generic features of the vascular branching pattern, thus, supporting the hypothesis that cell rearrangements play an essential role in sprouting angiogenesis. Furthermore, we predict that lower cell rearrangement leads to an imbalance between branching and sprout elongation. Since the computation of this statistic requires only individual cell trajectories, it can be computed for networks generated in biological experiments, making it a potential biomarker for pathological angiogenesis.Author summaryAngiogenesis, the process by which new blood vessels are formed by sprouting from the pre-existing vascular bed, plays a key role in both physiological and pathological processes, including tumour growth. The structure of a growing vascular network is determined by the coordinated behaviour of endothelial cells in response to various signalling cues. Recent experimental studies have highlighted the importance of cell rearrangements as a driver for sprout elongation. However, the functional role of this phenomenon remains unclear. We formulate a new multiscale model of angiogenesis which, by accounting explicitly for the complex dynamics of endothelial cells within growing angiogenic sprouts, is able to produce generic features of angiogenic structures (branching, chemotactic sensitivity, cell mixing, etc.) as emergent properties of its dynamics. We validate our model against experimental data and then use it to quantify the phenomenon of cell mixing in vascular networks generated by endothelial cells of different lineages. Our results show that there is a direct correlation between the time evolution of cell mixing in a growing vascular network and its branching structure, thus paving the way for understanding the functional role of cell rearrangements in angiogenesis.

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