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1 Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
* To whom correspondence should be addressed. E-mail: apopel{at}jhu.edu.
This study uses a computational model to characterize the myocardial deposition and retention of basic fibroblast growth factor (FGF-2) at the cellular level following an intracoronary administration of exogenous FGF-2. The model is applied to the in-situ conditions present within the myocardium of a dog for which the plasma pharmacokinetics resulting from the intracoronary injection of FGF-2 were recorded. Our estimates show that the processes involved in FGF-2 signaling are not diffusion-limited; rather, the response time is determined by the reaction times of FGF-2 binding to cell surface receptors. Additionally, the processes of receptor secretion and internalization are found to play crucial roles in the FGF-2 dynamics; future experiments are required to quantify these processes. The model predictions obtained in this study suggest that the intracoronary administration of FGF-2, via either single bolus or repetitive injections, causes a transient increase (time scale of hours) in myocardial FGF-2 if the endogenous level of free interstitial FGF-2 is low enough to allow the permeation of FGF-2 molecules from the microvascular space to the interstitial space. The model shows that the majority (64%) of the extracellular FGF-2 ligands are located within the interstitium, with similar fractions in the basement membrane and the extracellular matrix. Among the FGF-2 molecules found within the interstitium, 2% are free and 98% are bound to interstitial heparan sulfate proteoglycans (HSPGs). These results support the theory of extracellular control of the bioavailability of FGF-2 via dynamic storage of FGF-2 within the basement membrane and extracellular matrix.
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