Urokinase-induced smooth muscle cell responses require distinct signaling pathways: A role for the epidermal growth factor receptor

Elevated urokinase-like plasminogen activator (uPA) and decreased plasminogen activator inhibitor-1 (PAI-1) levels are predictors for restenosis. Matrix remodeling and smooth muscle cell responses are integrally linked. Changes in smooth muscle cell migration and proliferation are dependent on the extracellular matrix environment in which they are encased. Proteases such as uPA can effect smooth muscle cells and alter the matrix; their activity is controlled by a series of inhibitors (eg, PAI-1). The balance of activation and inhibition forms the basis of the proteolytic thermostat in the vessel wall. Understanding the biology of the proteolytic thermostat will allow for structured therapeutic interventions to control restenosis and thus improve patient care and avoid secondary interventions. Our study demonstrates that uPA is capable of inducing separate responses through more than one signaling pathway, in part, by transactivation of a nearby receptor for the unrelated ligand epidermal growth factor receptor (EGFR). Blockade of EGFR can inhibit both cell migration and proliferation induced by uPA. This is the first description of cross talk between uPA and EGFR in vascular smooth muscle cells. Targeting a pivotal receptor such as EGFR, which can be transactivated by both G-protein-coupled receptors and receptor tyrosine kinases, is an attractive molecular target to control restenosis.