Regulation of plasminogen activator inhibitor-1 secretion by growth factors in smooth muscle cells

Epithelioid-type vascular smooth muscle cells are metabolically active and secrete many proteases and protease inhibitors. We have. p previously cloned epithelioid-type smooth muscle cells from rat carotid arteries, and showed that polypeptide growth factors basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) could dose-dependently induce plasminogen activator inhibitor-1 (PAI-1) secretion from these cells. In the present study, we have used these cells to investigate the growth factor-induced signal transduction pathways leading to PAI-1 secretion. We report here that PAI-1 induction was dependent on protein kinase C (PKC) and tyrosine kinase but not on protein kinase A (PKA), ras and phosphoinositol-3-kinase inhibitor. Induction of PAI-1 by bFGF and PDGF was also accompanied by activation of a mitogen-activated protein kinase pathway involving Raf/Mek/Erk1/2, and the src family non-receptor tyrosine kinases. Syk, another non-receptor tyrosine kinase, on the contrary, behaved differently from src in that it was part of a pathway leading to PAI-1 induction by bFGF, but not when PDGF was used as the stimulating reagent. Activation of a PKA-dependent pathway(s) opposed PAI-1 induction. One mechanism for PKA activators to inhibit PAI-1 secretion was that they markedly inhibited the phosphorylations of Mek and mitogen-activated protein kinase that were up-regulated in the presence of bFGF and PDGF. (C) 2002 Lippincott Williams Wilkins.