Function and Regulation of the Vascular Cell Adhesion Molecule-l in TNF-Stimulated Endothelial Cells

The accumulation of circulating monocytes in the vessel wall is an important aspect of the pathogenesis of atherosclerosis and allied problems such as restenosis after percutaneous transluminal angioplasty (PTA). Three distinct steps can be distinguished in the stimulated accumulation of these cells. First there is an increased rolling, followed by firm adhesion, and finally migration of the monocytes in the direction of a chemotactic gradient. These different steps are regulated by specific endothelial cell adhesion molecules. In general rolling is mediated by the selectins, while immunoglobulin supergene family member vascular cell adhesion molecule (VCAM)-l specifically mediates rolling and fiml adhesion of monocytes. VCAM-I may thus enhance the local accumulation of monocytes even in the absence of seledin expression. In experimental models of atherosclerosis VCAM-I expression is an early feature of the atheromatous lesion, which suggests that VCAM-l plays a role in the initiation and progression of the atherosclerotic plaque. The expression of VCAM-l on endothelial cells is induced by the cytokine tumor necrosis factor a (TNF) and presumably regulated at the transcriptional level in part through the activation of the transcription factor nuclear factor (NF) KB. TNF stimulates intracellular signalling in endothelial cells through the production of lipid second messengers and mitogen activated protein kinase cascades. It has been hypothesized that reactive oxygen species (ROS), such as hydrogen peroxide, function as intracellular second messengers in the signal transduction of TNF. This putative role for ROS may comprise a novel mechanism of intracellular signalling next to protein phosphorylation. the cyclic nucleotide system, and signalling through the inositol phosphates and intracellular calcium. In the present thesis we have investigated the possible role of ROS as second messengers in the TNF stimulated expression of VCAM-l by endothelial cells.

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