Biomedical subjects

Renee J Filion

Publications and source records attributed to Renee J Filion.

3 recordsLinked to original sources

PubMed2004

Intracoronary administration of FGF-2: a computational model of myocardial deposition and retention.

This study uses a computational model to characterize the myocardial deposition and retention of basic fibroblast growth factor (FGF-2) at the cellular level after intracoronary (IC) 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 IC 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 time 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 IC administration of FGF-2 via either a single bolus or repetitive injections causes a transient increase (time scale of hours) in myocardial FGF-2 concentration if the endogenous level of free interstitial FGF-2 is low enough to allow permeation of FGF-2 molecules from the microvascular to the interstitial spaces. The model shows that the majority (64%) of the extracellular FGF-2 ligands are located within the interstitium, and similar fractions are found in the basement membrane and extracellular matrix. Among the FGF-2 molecules found within the interstitium, 2% are free and 98% are bound to interstitial heparan sulfate proteoglycans. 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.

Animals↗

PubMed2004

A reaction-diffusion model of basic fibroblast growth factor interactions with cell surface receptors.

Basic fibroblast growth factor (FGF-2) is a potent angiogenic growth factor involved in the development of diseases such as cancer, atherosclerosis, and heart and limb ischemia, as well as normal wound healing and tissue development. Despite being one of the most heavily studied angiogenic growth factors, the binding kinetics and signaling pathways of FGF-2 are still incompletely understood. In this study, we address the role of the low-affinity heparan sulfate proteoglycans (HSPGs), the identity of the minimal signaling complex leading to FGF-2 activity, and the importance of FGF-2 dimerization using a mathematical model of FGF-2 diffusion and ligand-receptor binding. Unique model features include the degradation of internalized cell surface species, the binding of a second FGF-2 ligand to a high-affinity FGF receptor (FGFR), and the dimerization of FGF-2 ligands. All experimentally determined reaction rates and diffusivity values are scaled to 37 degrees C. Our model results suggest that FGF-2-induced cellular response is the result of a temporal combination of triads (FGF-2/HSPG/FGFR complexes), double triads (2 FGF-2/HSPG/FGFR complexes), and FGF-2-bound HSPGs (FGF-2/HSPG complexes). Moreover, ligand dimerization is shown to potentially regulate FGF-2 activity by shifting the distribution of signaling complexes from the less stable triads to the more stable double triads.

Animals↗

PubMed2003

A finite difference model of O2 transport in aortic valve cusps: importance of intrinsic microcirculation.

Recent studies have reported the presence of a microcirculation within the tissue of aortic valves. To test the hypothesis that this vascular bed is needed to satisfy the oxygen demands of the cusp tissue, a two-dimensional (2D) finite difference model of oxygen diffusion was developed. The in vivo environment was modeled for vascular and avascular cusps using thickness data from precise radiographic measurements of fresh porcine valves, and O2 diffusivity (DO2) and O2 consumption (VO2) values from experimental data. The location and density of the cusp vasculature were determined by the model to prevent oxygen levels from falling to zero. Validation of the model was performed by simulation of the experimental measurements of cusp DO2 and VO2. For a test cusp with uniform thickness, the model returned simulated DO2 and VO2 measurements within 1.43% and 0.18% difference of the true parameter values, respectively. For native cusps, the simulated DO2 measurements were sensitive to thickness variations (-38 to +21% difference), whereas the VO2 measurements were minimally affected (8% difference). An improved DO2 measurement technique was found to reduce these errors to <5% and is recommended for analysis of experimental data. In the avascular case, the model predicted large regions of hypoxic tissue, whereas in the vascular case, the model predicted vessel locations and densities similar to what was experimentally observed in porcine cusps. Overall, the in vivo model developed in this study confirmed the need for an intrinsic microcirculation in the thicker basal regions of aortic cusps.

Animals↗