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arXiv · 1606.02167

Integrative modeling of sprout formation in angiogenesis: coupling the VEGFA-Notch signaling in a dynamic stalk-tip cell selection

Sotiris A. Prokopiou·Markus R. Owen·Helen M. Byrne·Safiyyah Ziyad·Courtney Domigan·M. Luisa Iruela-Arispe·Yi Jiang
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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.

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Sotiris A. Prokopiou, Markus R. Owen, Helen M. Byrne, Safiyyah Ziyad, Courtney Domigan, M. Luisa Iruela-Arispe, Yi Jiang. 2016-06-07. Integrative modeling of sprout formation in angiogenesis: coupling the VEGFA-Notch signaling in a dynamic stalk-tip cell selection. https://arxiv.org/abs/1606.02167

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