SIGNALING MECHANISMS IN THE REGULATION OF VASCULAR CELL-MIGRATION

The migration of arterial vascular smooth muscle cells (VSMC) is thoug ht to play a central role in atherogenesis and restenosis. The migrati on of several other cell types, including monocytes, T-lymphocytes and endothelial cells is also involved in the development of the mature a therosclerotic lesion. Several defined growth factors, cytokines and e xtracellular matrix components which are released at the sites of lesi ons have been implicated in the regulation of migration of VSMC and ot her lesion-associated cells. Platelet-derived growth factor BB-homodim er 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 (integrin s) for ECM components, organisation of the actin cytoskeleton and the turnover of focal adhesions are all key processes in cell locomotion a nd migration. The signal transduction pathways which mediate the chemo tactic effects of PDGF-BB and other migration factors on VSMC are unkn own, but several classes of cellular components are implicated includi ng components associated with focal adhesions, small GTP-binding prote ins of the rho family, and certain substrates of the PDGF beta-recepto r. Tyrosine phosphorylation of the novel focal adhesion-associated pro tein tyrosine kinase, p125 focal adhesion kinase (p125(FAK)), is regul ated by integrins and by several factors which alter actin cytoskeleta l organisation. Recent findings suggest that tyrosine phosphorylation of p125(FAK) and other focal adhesion-associated proteins may be impli cated in the chemotactic response of VSMC to PDGF-BB. The migratory re sponse to PDGF-BB may be dependent on both ligand isoform bio-availabi lity and on receptor-isotype expression as well as on down-stream sign alling events. Ultimately, cell migration in vivo will be determined b y a complex array of diverse extracellular molecules organised in inte rcellular paracrine/autocrine networks as well as multiple interacting intracellular signal transduction pathways.