1. Integrative modeling of sprout formation in angiogenesis: coupling the VEGFA-Notch signaling in a dynamic stalk-tip cell selection
- Author
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Prokopiou, Sotiris A., Owen, Markus R., Byrne, Helen M., Ziyad, Safiyyah, Domigan, Courtney, Iruela-Arispe, M. Luisa, and Jiang, Yi
- Subjects
endocrine system ,FOS: Biological sciences ,Cell Behavior (q-bio.CB) ,Quantitative Biology - Cell Behavior - Abstract
During angiogenesis, new blood vessels headed by a migrating endothelial tip cell sprout from pre-existing ones. This process is known to be regulated by two signaling pathways concurrently, vascular endothelial growth factor A (VEGFA) and Notch-Delta. Extracellular VEGFA activates the intracellular Notch-Delta pathway in nearby endothelial cells which results in endothelial (stalk, tip) differentiation. Retinal astrocytes appear to play a crucial role in polarizing new sprouts by secreting VEGFA. \emph{In vivo} retinal angiogenesis experiments in neonatal mouse generated quantitative data on daily cell counts and morphological data of vascular network expanding over fibronectin-rich matrix. Based on this set of data and other existing ones, we developed a cell-based, multiscale mathematical model using the cellular Potts model framework to investigate the sprout evolution by integrating the VEGFA and Notch-Delta signaling pathways. The model incorporates three levels of description: intracellular, intercellular, and extracellular. Starting with a single astrocyte embedded in a fibronectin-rich matrix, we use the model to assess different scenarios regarding VEGFA levels and its interaction with matrix proteins. Simulation results suggest that astrocyte-derived VEGFA gradients along with heterogeneous ECM reproduces sprouting morphology, and the extension speed is in agreement with experimental data in 7 days postnatal mouse retina. Results also reproduce empirical observations in sprouting angiogenesis, including anastomosis, dynamic tip cell competition, and sprout regression as a result of Notch blockade., Comment: 33 pages, 16 figures
- Published
- 2016
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