5-Hydroxytryptamine and Its Receptors in Systemic Vascular Walls

• Published in: Biological & pharmaceutical bulletin 2013/09/01, Vol.36(9), pp.1416-1419
• Main Authors: Machida, Takuji, Iizuka, Kenji, Hirafuji, Masahiko
• Format: Article
• Language: English
• Subjects: 5-hydroxytryptamine; angiogenesis; Animals; Endothelial Cells - physiology; Humans; Muscle, Smooth, Vascular - cytology; Myocytes, Smooth Muscle - physiology; Receptors, Serotonin - physiology; sarpogrelate; Serotonin - physiology; Serotonin Antagonists - pharmacology; Succinates - pharmacology; vascular endothelial cell; vascular smooth muscle cell
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b13-00344

5-Hydroxytryptamine (5-HT) in the bloodstream is largely contained in platelets and circulates throughout the entire vascular system. 5-HT released from activated platelets dramatically changes the function of vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). In VSMCs, 5-HT induces proliferation and migration via 5-HT2A receptors. These effects are further enhanced by vasoactive substances such as thromboxane A2 and angiotensin II. 5-HT2A receptor activation in VSMCs also causes both enhancement of prostaglandin I2 production by inducing cyclooxygenase-2 and reduction of nitric oxide (NO) by suppressing inducible NO synthase. Evidence showing that 5-HT in ECs plays a principal role in angiogenesis now exists. Stimulation of 5-HT1 and/or 5-HT2 receptors has been implicated in the angiogenic effect of 5-HT. The extracellular signal-regulated kinase and endothelial NO synthase (eNOS) activation-dependent pathways are involved in the mechanisms. Moreover, 5-HT4 receptors in ECs have been shown to also regulate angiogenesis. Recent reports show sarpogrelate, a selective antagonist of the 5-HT2A receptor, indirectly enhances the function of 5-HT1B receptors in ECs via inhibition of 5-HT2A receptors in VSMCs or platelets. This indirect action of 5-HT1B receptors in ECs may increase NO production derived from eNOS and a vasodilator response. Furthermore, sarpogrelate and other 5-HT2A receptor antagonists have been shown to reduce the constitutive activity of 5-HT2A receptors. It is believed that increasing evidence on the role of 5-HT receptors will contribute to the expansion of the clinical application of existing therapeutic drugs such as sarpogrelate, and to the development of new 5-HT receptor-related drugs for treating cardiovascular diseases.