Effect of Serotonin, Thromboxane A 2 , and Specific Receptor Antagonists on Vascular Smooth Muscle Cell Proliferation

Abstract

Background Restenosis is a major complication that limits the long-term efficacy of coronary angioplasty. Migration and proliferation of activated medial smooth muscle cells (SMCs) is considered an important mechanism in this process. Because at sites of vascular injury, aggregating platelets release both serotonin (5-HT) and thromboxane A 2 (TXA 2 ), we examined whether 5-HT and TXA 2 can induce SMC proliferation and 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 aortic SMCs by [ 3 H]thymidine incorporation into DNA and by cell counting. 5-HT induced SMC proliferation at a concentration of 100 nmol/L, whereas the effect of TXA 2 (U46619, a stable TXA 2 mimetic) on inducing proliferation of SMCs was observed at a concentration of 100 nmol/L. When these two mediators were added together, there was a synergistic interaction on inducing SMC proliferation even at subthreshold concentrations. The mitogenic effect of 5-HT and its synergistic interaction with TXA 2 on SMC proliferation was abolished by a 5-HT 2 receptor antagonist, LY281067, without affecting the contribution of TXA 2 . Similarly, the TXA 2 synthase inhibitor/receptor antagonist ridogrel abolished the mitogenic effect of TXA 2 and the interaction between 5-HT and TXA 2 without affecting the response to 5-HT. When LY281067 and ridogrel were used together, they abolished the mitogenic effects of 5-HT and TXA 2 . Conclusions At sites of vascular injury, platelet-induced SMC proliferation may also be modulated by nonpeptide growth mediators. A combination of a 5-HT 2 receptor antagonist and TXA 2 synthase inhibitor/receptor may be useful for attenuation of restenosis after angioplasty.