INDUCTION OF VASCULAR SMC PROLIFERATION BY UROKINASE INDICATES A NOVEL MECHANISM OF ACTION IN VASOPROLIFERATIVE DISORDERS

The urokinase-type plasminogen activator (UPA) and its receptor are ex pressed in the vasculature and are involved in cell migration and remo deling of the extracellular matrix in the neointima. Vessels with athe rosclerosis or neointimal hyperplasia, when compared with normal vesse ls, contain high UPA activity as well as increased levels of UPA recep tor. In this study, we have identified the stimulation of vascular smo oth muscle cell proliferation as a novel activity for UPA in the vesse l wall. High-molecular-weight-UPA (12-200 nmol/L range) stimulated DNA synthesis and cell proliferation, which was half that induced by feta l calf serum or by platelet-derived growth factor-BE. UPA did not indu ce growth of endothelial cells, and tissue-type plasminogen activator showed no activity on either cell type. Induction of proliferation req uired the complete UPA molecule but was independent of the proteolytic activity of UPA, whereas neither the amino-terminal fragment nor the catalytic domain by itself was mitogenic. UPA also stimulated c-fos/c- myc mRNA expression and mitogen-activated protein kinase activity in s mooth muscle cells. Blocking monoclonal antibodies against the UPA rec eptor and the enzymatic removal of receptors were ineffective in inhib iting the mitogenic effect of UPA, suggesting a UPA receptor-independe nt mechanism. Thus, we provide evidence for a novel function of UPA on vascular smooth muscle cell proliferation that, together with its pre viously documented involvement in regulating pericellular proteolysis- related events and cell migration, provides additional evidence for a role in the pathogenesis of atherosclerosis/restenosis.