title: An integrated mathematical model of thrombin-, histamine-and VEGF-mediated signalling in endothelial permeability.
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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Computation and Systems Biology, Singapore-MIT Alliance, National University of Singapore, E4-04-10, 4 Engineering Drive 3, 117576, Singapore.
authors.forename: X N
authors.initials: XN
authors.lastname: Wei
authors.forename: B C
authors.initials: BC
authors.lastname: Han
authors.forename: J X
authors.initials: JX
authors.lastname: Zhang
authors.forename: X H
authors.initials: XH
authors.lastname: Liu
authors.forename: C Y
authors.initials: CY
authors.lastname: Tan
authors.forename: Y Y
authors.initials: YY
authors.lastname: Jiang
authors.forename: B C
authors.initials: BC
authors.lastname: Low
authors.forename: B
authors.initials: B
authors.lastname: Tidor
authors.forename: Y Z
authors.initials: YZ
authors.lastname: Chen
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D004727:Endothelium / Q000166:cytology* / Q000378:metabolism*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006632:Histamine / Q000378:metabolism*; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008954:Models, Biological; D009124:Muscle Proteins / Q000378:metabolism; D018994:Myosin Light Chains / Q000378:metabolism; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D041681:NIH 3T3 Cells; D010539:Permeability; D010750:Phosphoproteins / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction; D013917:Thrombin / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D002147:Calmodulin; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D018994:Myosin Light Chains; D010750:Phosphoproteins; C491520:Ppp1r14a protein, mouse; D044463:Receptor, PAR-1; D042461:Vascular Endothelial Growth Factor A; D006632:Histamine; D015544:Inositol 1,4,5-Trisphosphate; D040301:Vascular Endothelial Growth Factor Receptor-2; D054460:rho-Associated Kinases; D009219:Myosin-Light-Chain Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D013917:Thrombin; D020741:rho GTP-Binding Proteins; D002118:Calcium