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Differential binding of VEGF isoforms to VEGF receptor 2 in the presence of neuropilin-1: a computational model

Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland

Submitted 3 December 2004 ; accepted in final form 2 February 2005

A comprehensive, biophysically accurate, computational model of vascular endothelial growth factor (VEGF) family member interactions with endothelial cell surface receptors was developed to study angiogenesis. Neuropilin-1 (NRP1) and the signaling VEGF receptor, VEGFR2, do not interact directly but are bridged by one VEGF isoform, VEGF₁₆₅. Using the model and published experimental data, we estimated the kinetic rate of this VEGFR2-NRP1 coupling in vitro. With the use of this rate, our model gives predictions in good quantitative agreement with several independent in vitro experiments involving VEGF₁₂₁ and VEGF₁₆₅ isoforms, confirming that VEGFR2-NRP1 coupling through VEGF₁₆₅ can fully explain the observed differences in receptor binding and phosphorylation in response to these isoforms. Model predictions also determine the mechanism of action of a commonly used NRP1 antibody and predict the results of potential future experiments. This is the first model to include VEGF isoforms or NRPs, and it is a necessary step toward a quantitative molecular level description of VEGF that can be extended to in vivo situations. The model has applications for both proangiogenic and antiangiogenic therapies, such as for heart disease and cancer, as well as in tissue engineering.

mathematical model; receptor coupling; angiogenesis; endothelial cell

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