Serotonin Transporter and Serotonin Receptors

Abstract

The nature of the primary defect responsible for triggering and maintaining pulmonary artery smooth muscle (PA-SMC) proliferation in pulmonary artery hypertension (PAH) is poorly understood but may be either an inherent characteristic of PA-SMCs or a secondary response to an external abnormality, such as upregulation of growth factors. The serotonin hypothesis of PAH originated in the 1960s after an outbreak of the disease was reported among patients taking the anorexigenic drugs aminorex. The anorexiant dexfenfluramine which inhibits 5-HT neuronal uptake, causes 5-HT platelet depletion, and increases plasma levels of 5-HT, was then shown to increase the relative risk of developing PAH in the adults. More recently, the incidence of persistent pulmonary hypertension of the newborn was shown to be increased by the use of selective 5-HT reuptake inhibitors taken in late pregnancy. Serotonin is a vasoconstrictor and a potent mitogen for pulmonary smooth muscle cells (PA-SMC), an effect which depends upon activity of both the 5-HT transporter (5-HTT) and the 5-HT receptors. Expression analysis of lung tissues from PAH patients undergoing lung transplantation revealed an increased expression of the 5-HT transporter (5-HTT) and an enhanced proliferative growth response of isolated pulmonary arterial smooth muscle cells (PASMC) to 5-HT. Serotonin is contained in platelets but is also synthesized by pulmonary endothelial cells which express tryptophan hydroxylase 1, the rate-limiting enzyme of 5-HT synthesis. While inhibitors of 5-HTT and of 5-HT2B receptors can reverse experimental PH, 5-HTT-overexpressing mice spontaneously develop PH. In patients with chronic lung disease, a close association has been found between a 5-HTT gene polymorphism and the severity of pulmonary hypertension. Agents capable of selectively inhibiting 5-HTT-mediated PA-SMC proliferation deserve to be investigated as potential treatments for pulmonary hypertension. However, the 5-HT pathway is still studied only on a preclinical level and the usefulness of drugs interacting with the 5-HT pathway remains to be established in human PAH.