Abstract
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.
Highlights
Vascular endothelial growth factor (VEGF) belongs to a family of cytokines that play an important role in angiogenesis – the formation of new capillaries from pre-existing vessels
VEGF is secreted by the myocytes into the interstitial space where it can bind to VEGF receptors VEGFR-1, VEGFR-2, and NRP-1 on the abluminal surface of the endothelial cells, as well as to glycosaminoglycan chains (GAG) in the basement membranes and extracellular matrix
We have extended the previously developed compartmental model of VEGF distribution in humans to investigate the VEGF distribution in the mouse
Summary
Vascular endothelial growth factor (VEGF) belongs to a family of cytokines that play an important role in angiogenesis – the formation of new capillaries from pre-existing vessels. A single-compartment model of the human tissue was initially developed to study the kinetic ligand-receptor interactions of multiple VEGF isoforms with endothelial cell surface receptors (VEGFR-1, VEGFR-2, NRP-1) and extracellular matrix binding sites [7] This model was later expanded to include three compartments, including a tumor compartment, to study tumor angiogenesis [8] and peripheral arterial disease [9]. Due to the large number of experimental studies performed in mice, including the work of Rudge et al, and given the vast amount of experimental data available from these studies, we have developed a whole-body computational model of VEGF distribution in the mouse, expanding our previous models of VEGF distribution in human [8,18,19,20] In this model we take into account VEGF receptor expression on both luminal and abluminal surfaces of endothelial cells, and expression of neuropilin-1 on endothelial cells and myocytes. The mouse model of VEGF distribution can be used in tandem with the previously developed human models to compare the two systems and to scale-up pro- and anti-angiogenic therapeutics for translation from mouse studies (preclinical studies) to human studies (clinical trials)
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