Invited Symposium: Signal Transduction in Endothelium: Mechano-Sensing, Ion Channels and Intracellular Calcium
Shear stress, complex flow pattern, areal strain, and other forms of mechanical stimuli can modulate gene expression in a variety of cells, including vascular endothelial cells (EC). The modulation of gene expression by mechanical stimuli involves the activation of cis-elements in the promoter region of the gene by transcription factors activated by signal transduction pathways. The effects of mechanical stimuli on gene expression and signal transduction have been studied in several types of flow channels and stretch devices in vitro. Laminar shear stress activates a number of genes in cultured EC, including that encoding for monocyte chemotactic protein-1 (MCP-1), which has TPA responsive element (TRE) as the cis-element. Studies on phosphorylation of signaling molecules and using negative mutants demonstrate that FAK (focal adhesion kinase) - Ras - JNK (N-terminal Jun kinase) signaling is a major pathway mediating the shear-induced transient expression of the MCP-1 gene. Integrins and cytoskeleton, as well as receptor tyrosine kinases, also participate in the signaling. Time course studies indicate the sequential activation of these and other signaling molecules, culminating in the activation of gene expression. There is evidence that dephosphorylation of the signaling molecules may contribute to the transient nature of the shear-activation. A dominant negative mutant of Ras has been shown to be effective in preventing intimal proliferation in a rat experimental model of re-stenosis following balloon injury. With the use of a step-flow channel, the flow reattachment area was shown to have an increase in DNA synthesis, an enhanced promoter activity of the cyclin-dependent kinase cdc2, and EC apoptosis. Thus, the EC monolayer at sites of complex flow, e.g., the branch points of the arterial tree, maintains its confluence at the expense of accelerations of mitosis and apoptosis, with an attendant increase in macromolecular permeability. In contrast, sustained laminar shear stress causes the modulation of expression of genes to arrest the EC cell cycle, and this may provide a molecular basis for the protective function of laminar shear stress in the straight part of the arterial tree against atherogenesis. The results of these studies indicate that the effects of mechanical stimuli on signal transduction and gene expression play significant roles in the regulation of many physiological functions and in the pathophysiological changes in disease.
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|Chien, Shu; (1998). Effects of Mechanical Forces on Signal Transduction and Gene Expression in Endothelial Cells. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/nilius/chien0859/index.html|
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