Mechanical strain-induced regulation of vascular endothelial growth factor production by human vascular smooth muscle cells

The present thesis investigates the effect of cyclical mechanical strain on the expression of vascular endothelial growth factor (VEGF); a potent cytokine produced by human vascular smooth muscle cells (VSMC). The initial investigations observed the expression of VEGF mRNA and peptide over time and then the effect of increasing the magnitude of strain applied to the cells.;The second area of study was to identify the effect of strain on a candidate intracellular signalling pathway, the mitogen activated protein kinase (MAPK) cascade. The experiments observed the effect of strain on the level of phosphorylated MAPK within the cells and the actual activity of MAPK isolated from cultured human VSMC. The effect of a MAPK pathway inhibitor (PD98059) on the phosphorylated peptide activity was also analysed.;The data submitted in this thesis demonstrates that the expression of VEGF mRNA and peptide are increased in a dose-dependent manner when exposed to cyclical mechanical strain and that the level of phosphorylated MAPK increases likewise. Furthermore, the addition of a MAPK inhibitor not only reduces the level of MAPK activation, but also the expression of VEGF. Taken together, these data identify a potential mechanism whereby strain can directly effect vascular permeability by regulating the expression of VEGF peptide through the MAP kinase cascade.