Abstract
BackgroundEndothelial permeability is involved in injury, inflammation, diabetes and cancer. It is partly regulated by the thrombin-, histamine-, and VEGF-mediated myosin-light-chain (MLC) activation pathways. While these pathways have been investigated, questions such as temporal effects and the dynamics of multi-mediator regulation remain to be fully studied. Mathematical modeling of these pathways facilitates such studies. Based on the published ordinary differential equation models of the pathway components, we developed an integrated model of thrombin-, histamine-, and VEGF-mediated MLC activation pathways.ResultsOur model was validated against experimental data for calcium release and thrombin-, histamine-, and VEGF-mediated MLC activation. The simulated effects of PAR-1, Rho GTPase, ROCK, VEGF and VEGFR2 over-expression on MLC activation, and the collective modulation by thrombin and histamine are consistent with experimental findings. Our model was used to predict enhanced MLC activation by CPI-17 over-expression and by synergistic action of thrombin and VEGF at low mediator levels. These may have impact in endothelial permeability and metastasis in cancer patients with blood coagulation.ConclusionOur model was validated against a number of experimental findings and the observed synergistic effects of low concentrations of thrombin and histamine in mediating the activation of MLC. It can be used to predict the effects of altered pathway components, collective actions of multiple mediators and the potential impact to various diseases. Similar to the published models of other pathways, our model can potentially be used to identify important disease genes through sensitivity analysis of signalling components.
Highlights
Endothelial permeability is involved in injury, inflammation, diabetes and cancer
We developed a mathematical model that integrates thrombin, histamine, and vascular endothelial growth factor (VEGF) mediated signalling in endothelial permeability by extending the published ordinary differential equation (ODE) models of the thrombin-mediated pathway and Ca2+-CaM and Myosin light chain kinase (MLCK) activation of MLC [15,16,18,21]
Model validation with experimental studies of the regulation of MLC activation, calcium release, and Rho activation by thrombin Our simulation model was first validated by determining whether the simulation results were consistent with experimental observations of MLC activation and calcium release by the single mediator thrombin
Summary
Endothelial permeability is involved in injury, inflammation, diabetes and cancer It is partly regulated by the thrombin-, histamine-, and VEGF-mediated myosin-light-chain (MLC) activation pathways. VEGF, released in diabetic retinopathy, I-R injury, vasculogenesis, angiogenesis, and tumor development and metastasis, causes endothelial permeability to enable extravasation of fluids and solutes and intravasation of tumor cells [8,9,10] These three key mediators stimulate their respective receptors on endothelial cells to individually and collectively activate Ca2+, Rho GTPase/ROCK, and Myosin light chain kinase (MLCK) signalling pathways that subsequently activate myosin light chain (MLC) to induce cytoskeleton contraction in endothelial cells and dissociation of cell-cell junctions, resulting in endothelial hyper-permeability [4,11]. Another question is how multiple mediators under certain complicated inflammatory conditions collectively reduce the effectiveness of antagonizing agents directed at individual mediator-mediated signalling [4]
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