The serotonin hypothesis in pulmonary hypertension revisited: targets for novel therapies (2017 Grover Conference Series)

Abstract

Increased synthesis of serotonin and/or activity of serotonin in pulmonary arteries has been implicated in the pathobiology of pulmonary arterial hypertension (PAH). The incidence of PAH associated with diet pills such as aminorex, fenfluramine, and chlorphentermine initially led to the "serotonin hypothesis of pulmonary hypertension." Over the last couple of decades there has been an accumulation of convincing evidence that targeting serotonin synthesis or signaling is a novel and promising approach to the development of novel therapies for PAH. Pulmonary endothelial serotonin synthesis via tryptophan hydroxlase 1 (TPH1) is increased in patients with PAH and serotonin can act in a paracrine fashion on underlying pulmonary arterial smooth muscle cells (PASMCs), In humans, serotonin can enter PASMCs via the serotonin transporter (SERT) or activate the 5-HT1B receptor; 5-HT1B activation and SERT activity cooperate to induce PASMC contraction and proliferation via activation of downstream proliferative and contractile signaling pathways. Here we will review the current status of the serotonin hypothesis and discuss potential and novel therapeutic targets.

Keywords: 5-HT1B receptor; pulmonary hypertension; serotonin; tryptophan hydroxylase 1.

Fig. 1.

Serotonin is synthesized from L-tryptophan through the activity of TPH which converts L-tryptophan to 5-HT. This is converted to serotonin by 5-hydroxytryptophandecarboxylase and aromatic L-amino acid decarboxylase. Serotonin is metabolized to 5-HIAA via MAO and aldehyde dehydrogenase.

Fig. 2.

Serotonin synthesis via tryptophan hydroxylase 1 (TPH1) is increased in pulmonary artery endothelial cells (PAECs) from rodent models of PH (inset showing a small pulmonary artery from a control and hypoxic rat with TPH1 staining in the PAECs) and patients with PAH. Serotonin can act in a paracrine fashion on underlying PASMCs, facilitated by myoendothelial gap junctions (connexion intercellular channels). Serotonin can enter the PASMC via the Serotonin transporter (SERT) or activate serotonin receptors. The important receptor in the human pulmonary arterial smooth muscle cell (PASMC) is the 5-HT1B receptor, regulated by microRNA96 (miR96) such that it is upregulated (by decreased miR96 expression) in female PAH patient PASMCs. 5-HT1B activation and SERT activity cooperate to induce PASMC contraction and proliferation via increased ROS and activation of downstream signaling pathways such as MAPK and rho-kinase (ROCK). These can also facilitate nuclear growth factors such as GATA-4. Increased serotonin can facilitate a pulmonary hypertensive phenotype in BMPR2-/+ mice via decreased BMPR2 signaling.