Effect of serotonin, thromboxane A2, and specific receptor antagonists on vascular smooth muscle cell proliferation.
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 A2 (TXA2), we examined whether 5-HT and TXA2 can induce SMC proliferation and whether there is synergistic interaction between these two mediators.


RESULTS
The mitogenic effects of 5-HT and TXA2 either alone or in combination was examined in serum-free medium on canine aortic SMCs by [3H]thymidine incorporation into DNA and by cell counting. 5-HT induced SMC proliferation at a concentration of 100 nmol/L, whereas the effect of TXA2 (U46619, a stable TXA2 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 TXA2 on SMC proliferation was abolished by a 5-HT2 receptor antagonist, LY281067, without affecting the contribution of TXA2. Similarly, the TXA2 synthase inhibitor/receptor antagonist ridogrel abolished the mitogenic effect of TXA2 and the interaction between 5-HT and TXA2 without affecting the response to 5-HT. When LY281067 and ridogrel were used together, they abolished the mitogenic effects of 5-HT and TXA2.


CONCLUSIONS
At sites of vascular injury, platelet-induced SMC proliferation may also be modulated by nonpeptide growth mediators. A combination of a 5-HT2 receptor antagonist and TXA2 synthase inhibitor/receptor may be useful for attenuation of restenosis after angioplasty.
Pakala
R
R
Department of Internal Medicine, University of Texas Houston Medical School, 77030, USA.
Willerson
J T
JT
Benedict
C R
CR
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004285:Dogs; D004357:Drug Synergism; D008237:Lysergic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D011985:Receptors, Serotonin / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism
D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D012701:Serotonin; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D004247:DNA; D008237:Lysergic Acid; C054583:sergolexole; D013936:Thymidine