A computational model of fibroblast growth factor-2 binding to endothelial cells under fluid flow

Fibroblast growth factor-2 (FGF2) is an angiogenic growth factor that binds to cell surface receptors (FGFR) and heparan sulfate proteoglycans (HSPG), as well as HSPG in the basement membrane. FGF2 plays a critical role in angiogenesis, yet clinical FGF2 trials demonstrated limited success perhaps due to inadequate understanding of FGF2 binding in physiological conditions. We developed a computational model of FGF2 binding to isolated (HSPG or FGFR) or combined (HSPG and FGFR) binding sites under physiological fluid flow and predicted the effects of FGF2 concentration, binding site density, fluid flow rate, and delivery mode (continuous vs. bolus) on FGF2 complex formation. The isolated binding site models showed increased binding with FGF2 and binding site density. However, in the triad model, increasing FGF2 concentration decreased triads (FGF2-HSPG-FGFR) and increased FGF2-HSPG complexes. Fluid flow decreased time to equilibrium and dissociation in isolated binding site models, yet flow effect in the triad model depended on binding site density. Similarly, FGF2 capture and complex stability in bolus delivery depended on bolus size, flow rate, association and dissociation rate constants, as well as binding site density. This model shows the integrated effects of FGF2 binding stoichiometry, fluid flow, and delivery mode, and enhances our understanding of FGF2 complex formation under physiological conditions.