A Two-Compartment Model of VEGF Distribution in the Mouse

Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
PLoS ONE (Impact Factor: 3.23). 11/2011; 6(11):e27514. DOI: 10.1371/journal.pone.0027514
Source: PubMed


Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis – the growth of new microvessels from existing microvasculature. Angiogenesis is a complex process involving numerous molecular species, and to better understand it, a systems biology approach is necessary. In vivo preclinical experiments in the area of angiogenesis are typically performed in mouse models; this includes drug development targeting VEGF. Thus, to quantitatively interpret such experimental results, a computational model of VEGF distribution in the mouse can be beneficial. In this paper, we present an in silico model of VEGF distribution in mice, determine model parameters from existing experimental data, conduct sensitivity analysis, and test the validity of the model.
The multiscale model is comprised of two compartments: blood and tissue. The model accounts for interactions between two major VEGF isoforms (VEGF120 and VEGF164) and their endothelial cell receptors VEGFR-1, VEGFR-2, and co-receptor neuropilin-1. Neuropilin-1 is also expressed on the surface of parenchymal cells. The model includes transcapillary macromolecular permeability, lymphatic transport, and macromolecular plasma clearance. Simulations predict that the concentration of unbound VEGF in the tissue is approximately 50-fold greater than in the blood. These concentrations are highly dependent on the VEGF secretion rate. Parameter estimation was performed to fit the simulation results to available experimental data, and permitted the estimation of VEGF secretion rate in healthy tissue, which is difficult to measure experimentally. The model can provide quantitative interpretation of preclinical animal data and may be used in conjunction with experimental studies in the development of pro- and anti-angiogenic agents. The model approximates the normal tissue as skeletal muscle and includes endothelial cells to represent the vasculature. As the VEGF system becomes better characterized in other tissues and cell types, the model can be expanded to include additional compartments and vascular elements.

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    • "For these reasons, computational models of angiogenesis have been developed to simulate the process and provide a framework for generating and testing hypotheses of VEGF-driven processes [11], [15], [21]. Models have aided in the development of novel and effective anti-angiogenic therapeutics that target VEGF regulation and receptors [16], [10], [28]. Advancing these computational approaches combined with progress in in vitro experimental studies will shed light on these issues by providing an effective framework for generating and testing hypotheses related to VEGF regulation and transport in the tissue [21]. "

    CIBCB 2015; 08/2015
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    • "Although we know that antiangiogenic drugs such as sunitinib affect endothelial cell migration and proliferation, its mechanism of action is not completely understood. Computational models can predict the dynamics of free and bound VEGF in vivo, but the current models assume that the number of cell surface receptors remains constant;24–28 thus, the models are limited in their predictions of antiangiogenic therapy. Previous studies have been effective at measuring the numbers of VEGFRs in vitro29 and in vivo.30,31 "
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