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1 Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
* To whom correspondence should be addressed. E-mail: feilim{at}jhu.edu.
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 estimate the kinetic rate of this VEGFR2-NRP1 coupling in vitro. Using 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 Neuropilins and it is a necessary step towards a quantitative molecular-level description of VEGF that can be extended to in vivo situations. The model has applications for both pro-angiogenic and anti-angiogenic therapies, such as for heart disease and cancer, as well as in tissue engineering.
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