An Integrated Mathematical Model of Thrombin-, Histamine-and VEGF-Mediated Signalling in Endothelial Permeability
1 Computation and Systems Biology, Singapore-MIT Alliance, National University of Singapore, E4-04-10, 4 Engineering Drive 3, 117576, Singapore
2 The Guangdong Provincial Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen, China
3 Bioinformatics and Drug Design Group, Department of Pharmacy and Center of Computational Science and Engineering, National University of Singapore, Blk S16, Level 8, 3 Science Drive, 117543, Singapore
4 Research Centre of Excellence in Mechanobiology Institute, Cell Signalling and Developmental Biology Laboratory, Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, 117543, Singapore
5 Department of Biological Engineering, Department of Electrical Engineering & Computer Science, Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Room 32-212, Cambridge, MA 02139-4307 USA
6 Singapore-MIT Alliance for Research and Technology, Blk S16, Level 7, 3 Science Drive 2, 117543, Singapore
BMC Systems Biology 2011, 5:112 doi:10.1186/1752-0509-5-112Published: 15 July 2011
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.
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.
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.