an integrated mathematical model of thrombin-, histamine-and vegf-mediated signalling in endothelial permeability一个集成的数学模型,凝血酶,组胺和vegf-mediated内皮通透性的信号.pdfVIP

Wei et al. BMC Systems Biology 2011, 5:112 /1752-0509/5/112 RESEARCH ARTICLE Open Access An Integrated Mathematical Model of Thrombin-, Histamine-and VEGF-Mediated Signalling in Endothelial Permeability 1,2,3 1,3 3 3 2 2 1,4 1,5,6 1,2,3* XN Wei , BC Han , JX Zhang , XH Liu , CY Tan , YY Jiang , BC Low , B Tidor and YZ Chen Abstract Background: 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. 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. Results: Our 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. Conclusion: Our model was validated against a number of experimental findings and the observed synergistic effects of low concentrations of thrombin and histamine in med