EFFECT OF SEROTONIN, THROMBOXANE A(2), AND SPECIFIC RECEPTOR ANTAGONISTS ON VASCULAR SMOOTH-MUSCLE CELL-PROLIFERATION

Background Restenosis is a major complication that limits the long-ter m efficacy of coronary angioplasty. Migration and proliferation of act ivated medial smooth muscle cells (SMCs) is considered an important me chanism in this process. Because at sites of vascular injury, aggregat ing platelets release both serotonin (5-HT) and thromboxane A(2) (TXA( 2)), we examined whether 5-HT and TXA, can induce SMC proliferation an d whether there is synergistic interaction between these two mediators . Methods and Results The mitogenic effects of 5-HT and TXA(2) either alone or in combination was examined in serum-free medium on canine ao rtic SMCs by [H-3]thymidine incorporation into DNA and by cell countin g. 5-HT induced SMC proliferation at a concentration of 100 nmol/L, wh ereas the effect of TXA(2) (U46619, a stable TXA(2) mimetic) on induci ng proliferation of SMCs was observed at a concentration of 100 nmol/L . When these two mediators were added together, there was a synergisti c interaction on inducing SMC proliferation even at subthreshold conce ntrations. The mitogenic effect of 5-HT and its synergistic interactio n with TXA(2) on SMC proliferation was abolished by a 5-HT2 receptor a ntagonist, LY281067, without affecting the contribution of TXA(2). Sim ilarly, the TXA(2) synthase inhibitor/receptor antagonist ridogrel abo lished the mitogenic effect of TXA, and the interaction between 5-HT a nd TXA(2) without affecting the response to 5-HT. When LY281067 and ri dogrel were used together, they abolished the mitogenic effects of 5-H T and TXA(2). Conclusions At sites of vascular injury, platelet-induce d SMC proliferation may also be modulated by nonpeptide growth mediato rs. A combination of a 5-HT2 receptor antagonist and TXA(2) synthase i nhibitor/receptor may be useful for attenuation of restenosis after an gioplasty.