SIGNALING MECHANISMS IN THE REGULATION OF VASCULAR CELL-MIGRATION

The migration of arterial vascular smooth muscle cells (VSMC) is thought to play a central role in atherogenesis and restenosis. The migration of several other cell types, including monocytes, T-lymphocytes and endothelial cells is also involved in the development of the mature atherosclerotic lesion. Several defined growth factors, cytokines and extracellular matrix components which are released at the sites of lesions have been implicated in the regulation of migration of VSMC and other lesion-associated cells. Platelet-derived growth factor BB-homodimer of PDGF (PDGF-BB) is strongly implicated in neo-intima formation in vivo and is the most potent known chemoattractant for VSMC in vitro. Dynamic interactions between cell surface adhesive receptors (integrins) for ECM components, organisation of the actin cytoskeleton and the turnover of focal adhesions are all key processes in cell locomotion and migration. The signal transduction pathways which mediate the chemotactic effects of PDGF-BB and other migration factors on VSMC are unknown, but several classes of cellular components are implicated including components associated with focal adhesions, small GTP-binding proteins of the rho family, and certain substrates of the PDGF beta-receptor. Tyrosine phosphorylation of the novel focal adhesion-associated protein tyrosine kinase, p125 focal adhesion kinase (p125(FAK)), is regulated by integrins and by several factors which alter actin cytoskeletal organisation. Recent findings suggest that tyrosine phosphorylation of p125(FAK) and other focal adhesion-associated proteins may be implicated in the chemotactic response of VSMC to PDGF-BB. The migratory response to PDGF-BB may be dependent on both ligand isoform bio-availability and on receptor-isotype expression as well as on down-stream signalling events. Ultimately, cell migration in vivo will be determined by a complex array of diverse extracellular molecules organised in intercellular paracrine/autocrine networks as well as multiple interacting intracellular signal transduction pathways.