Effects of heparin and related sulfated polysaccharides on tissue factor expression induced by mitogenic and non-mitogenic factors in human vascular smooth muscle cells

Smooth muscle cells (SMCs) of the intima are generally quiescent and non pr oliferative. Their proliferation due to different stimulations occurs in my ointimal hyperplasia and is regularly present in atherogenesis or after tra nsluminal angioplasty leading to vascular occlusive stenosis. In the course of these pathologies, the Tissue Factor (TF) synthesis was upregulated and rapidly expressed at the membrane of the SMCs. Heparin is known to inhibit SMCs proliferation induced by FCS. We evaluated the inhibitory effect of h eparin on the expression of TF induced by various mitogenic (FCS, PDGF-BB a nd EGF) and nonmitogenic (bacterial LPS) agents. Inhibition by heparin of S MCs proliferation induced by the same agonists was also determined. Quiescent human vascular SMCs from normal adult arteries were treated for 1 h by heparin and related sulfated polysaccharides before stimulation by th e agonists. All the agonists up-regulated the expression of TF antigen and activity. TF expression induced by the growth factors was inhibited by hepa rin (IC 50: 10-30 mu g/ml), and other sulfated polysaccharides (IC 50: 1-5 mu g/ml). SMCs proliferation, late activation of the extracellular signal-r egulated kinases (ERK1/2), and PKC activity were inhibited by heparin (IC 5 0: 30-50 mu g/ml) in SMCs stimulated by FCS but not in SMCs treated by PDGF or EGF. In contrast, heparin had no effect on LPS-induced TF expression no r on LPS-induced PKC activation. These results indicate that, besides its w ell known effect on SMC proliferation, heparin displays an inhibitory effec t on cell mediated blood clotting processes through regulation of the TF ex pression.