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

TL;DR

This paper presents a multiscale mathematical model integrating VEGFA and Notch-Delta signaling pathways to simulate and analyze sprout formation during angiogenesis, validated by experimental data from neonatal mouse retina.

Contribution

It introduces a comprehensive cell-based model combining intracellular, intercellular, and extracellular dynamics to study angiogenic sprouting.

Findings

Model reproduces sprouting morphology and extension speed.

Simulates tip cell competition and sprout regression.

Aligns with experimental observations in mouse retina.

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.