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1 Department of Biomedical Engineering, School of Medicine,, Johns Hopkins University, Baltimore, Maryland 21205, USA
* To whom correspondence should be addressed. E-mail: feilim{at}jhu.edu.
Placental Growth Factor (PlGF) competes with Vascular Endothelial Growth Factor (VEGF) for binding to VEGF Receptor-1 (VEGFR1), but does not bind VEGFR2. Experiments show that PlGF can augment the response to VEGF in pathological angiogenesis and in models of endothelial cell survival, migration and proliferation. This synergy has been hypothesized to be due to a combination of: signaling by PlGF through VEGFR1; and displacement of VEGF from VEGFR1 to VEGFR2 by PlGF, causing increased signaling through VEGFR2. In this study, the relative contribution of PlGF-induced VEGF displacement to the synergy is quantified using a mathematical model of ligand-receptor binding to examine the effect on ligand-receptor complex formation of VEGF and PlGF acting together. Parameters specific to the VEGF-PlGF system are used, based on existing data. The model is used to simulate, in silico, a specific in vitro experiment in which VEGF-PlGF synergy is observed. We show that while a significant change in the formation of endothelial surface growth factor-VEGFR1 complexes is predicted in the presence of PlGF, the number of VEGFR2-containing signaling complexes is relatively unchanged; these results were shown to be robust to significant variation in the parameters of the model. Synergistic effects observed in that experiment thus appear not to be due to VEGF displacement, but to a shift from VEGF-VEGFR1 to PlGF-VEGFR1 complexes and an increase in total VEGFR1 complexes. These results suggest that VEGFR1 signaling can be functional in adult-derived endothelial cells.
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