5-Hydroxytryptamine and Its Receptors in Systemic Vascular Walls

Abstract

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.

Localization of the 5‐hydroxytryptamine 4 receptor in equine enteric neurons and extrinsic sensory fibers

“…In the present study, endothelial cells of small vessels expressed 5‐HT 4 ‐IR. This finding is consistent with studies indicating that 5‐HT 4 mRNA (together with 5‐HT 1 , 5‐HT 2 , and 5‐HT 7 mRNA) is expressed by endothelial and vascular smooth muscle cells . Furthermore, it is known that endothelial 5‐HT 4 regulates angiogenesis and that 5‐HT 4 agonist mosapride can inhibit proliferation and migration of endothelial cells in the human umbilical vein …”

Mechanisms mediating nitroglycerin-induced delayed-onset hyperalgesia in the rat

“…While systemically administered sumatriptan did not affect thermal or mechanical nociceptive threshold, or inflammatory hyperalgesia (Nikai et al, 2008), this may require a neurovascular component to the peripheral mechanisms generating allodynia/hyperalgesia. Thus, we have previously demonstrated (Joseph and Levine, 2012a) that sumatriptan administered at peripheral sites inhibits stimulus-dependent mechanical hyperalgesia by acting on 5-HT receptors located on endothelial cells (Machida et al, 2013); the data from the current study are consistent with this explanation. This model of GTN-induced hyperalgesia has advantages over other pre-clinical models in that it allows for the rapid screening of candidate therapeutic agents and has the potential to evaluate the effect of local modulatory interventions on nociception in an awake behaving animal.…”

5-HT1D receptor inhibits renal sympathetic neurotransmission by nitric oxide pathway in anesthetized rats

“…In agreement with this suggestion: (i) the release of NO by endothelium is determined by different mechanisms and substances, like serotonin [49]. (ii) The vasorelaxant actions by activation of 5-HT 1 receptors have been linked with the NO pathway [50][51][52][53][54]. iii) We have already demonstrated the NO involvement in inhibitory actions of total sympathetic outflow in pithed rats [48,55].…”