Genetics predict that happloinsufficiency of the BMPR2 receptor and over activity of the serotonin transporter are involved in the pathogenesis of pulmonary hypertension. Intriguingly, recent evidence suggests that the downstream signalling pathways of these proteins interact and co-operate to promote pulmonary vascular remodelling. There is also evidence that these pathways impinge on potassium channel function. This symposium has unravelled and discussed these novel interactions in the setting of pulmonary vascular remodelling. The serotonin system has been implicated in the development of pulmonary arterial hypertension (PAH) since the 1960s when the diet pill aminorex, an indirect serotinergic agent, was associated with the development of PAH. Serotonin is synthesised by the pulmonary vascular endothelium via the activity of tryptophan hydroxylase 1 (TPH1) and likely acts on underlying pulmonary artery smooth muscle cells (PASMCs) and fibroblasts in a paracrine fashion. It can cause vasoconstriction by activation of the 5-HT1B (1) or 5-HT2A receptor or it can enter the PASMCs via the serotonin transporter (SERT) to induce proliferation (2). Over-expression of SERT has been associated with the clinical development of PAH and we have recently shown that mice over-expressing SERT (SERT+ mice) are predisposed to hypoxia-induced PAH (3). In fibroblasts derived from SERT+ mice, we have demonstrated that activation of the 5-HT2A receptor induces downstream stimulation of p38 map kinase and proliferation which provides a mechanism for this phenotype. Clearly polymorphisms in the BMPR2 receptor alone do not account for the expression of the PAH phenotype and a ‘second hit’ is required and serotonin is an attractive candidate. Indeed, serotonin infusion can uncover a PAH phenotype in BMPR2+/- mice via inhibition of SMAD signalling (4). Serotonin can also inhibit Kv1.5 channel activity which would facilitate the vascular effects of inhibition of these channels. Serotonin can also induce mitogen activated protein kinases in pulmonary fibroblasts and this effect can be inhibited by inhibition of rho kinase, another potentially important mediator of pulmonary arterial proliferation and contraction. Recently, over-expression of TPH1 has been observed in pulmonary endothelial cells in patients with PAH and we have recently shown the development of hypoxia-induced PAH is ablated in mice deficient in TPH1 (Tph1-/- mice)(5). This is due to inhibition of pulmonary vascular remodelling rather than a decrease in pulmonary vascular reactivity. Furthermore, TPH1 expression in pulmonary endothelial cells is induced by hypoxia in mice. Hence evidence suggests that serotonin could play a role in critical proliferative pathways, inactivation of potassium channels, the expression of a PAH phenotype associated with BMPR2 happloinsifficiency as well as hypoxia-induced pulmonary vascular remodelling. The SERT, the 5-HT1B receptor and TPH1 are all potential novel therapeutic targets for the treatment of PAH.