A multiscale model of complex endothelial cell dynamics in early angiogenesis

PLoS Comput Biol. 2021 Jan 7;17(1):e1008055. doi: 10.1371/journal.pcbi.1008055. eCollection 2021 Jan.

Abstract

We 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / physiology
  • Cell Line
  • Cell Movement / physiology
  • Cells, Cultured
  • Endothelial Cells* / cytology
  • Endothelial Cells* / physiology
  • Mice
  • Models, Biological*
  • Neovascularization, Pathologic / physiopathology
  • Neovascularization, Physiologic / physiology*
  • Signal Transduction / physiology
  • Transcriptome / physiology

Grants and funding

This work is supported by a grant of the Obra Social La Caixa Foundation on Collaborative Mathematics awarded to the Centre de Recerca Matemàtica through a scholarship awarded to D.S. D.S. and T.A. have been partially funded by the CERCA Programme of the Generalitat de Catalunya. They also acknowledge MINECO (https://www.ciencia.gob.es/) for funding under grants MTM2015-71509-C2-1-R and RTI2018-098322-B-I00. D.S. and T.A. participate in project 2017SGR01735 which was awarded by AGAUR (https://agaur.gencat.cat/en/inici/index.html) but with no actual funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.