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In addition to its key function as a clotting enzyme, factor Xa (FXa) also elicits cellular effects. In cultured human venous smooth muscle cells (SMCs), FXa induced a mitogenic response that was independent of thrombin and platelet-derived growth factor (PDGF). Unfractionated heparin (UFH) as well as low molecular weight heparin (LMWH) (enoxaparin) inhibited the mitogenic effects of FXa, thrombin and fetal calf serum (FCS), but did not reduce mitogenesis induced by PDGF. Similarly, both UFH and LMWH inhibited the activation of extracellular signal-regulated kinase (ERK-1/2) by FXa, thrombin and FCS, but not by PDGF. This indicates that heparins can influence cellular signaling in SMC via an antithrombin-II (AT-III)-independent mechanism. The inhibition of ERK-1/2 correlated with the inhibition of mitogenesis by the heparins. Thus, the inhibition of ERK-1/2 phosphorylation by heparins might predict an antimitogenai response in this system.