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A role for the serotonin transporter in hypoxia-induced pulmonary hypertension
Barry L. Fanburg and Sheu-Ling Lee
Pulmonary and Critical Care Division, New England Medical Center, Boston, Massachusetts, USA
Address correspondence to: Barry L. Fanburg, Pulmonary and Critical Care Division, New England Medical Center, 750 Washington Street, #257, Boston, Massachusetts 02111, USA. Phone: (617) 636-5871; Fax: (617) 636-5953; E-mail: bfanburg@lifespan.org.
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Pulmonary and Critical Care Division, New England Medical Center, Boston, Massachusetts, USA
Address correspondence to: Barry L. Fanburg, Pulmonary and Critical Care Division, New England Medical Center, 750 Washington Street, #257, Boston, Massachusetts 02111, USA. Phone: (617) 636-5871; Fax: (617) 636-5953; E-mail: bfanburg@lifespan.org.
Find articles by Lee, S. in: PubMed | Google Scholar
Published June 1, 2000 - More info
J Clin Invest. 2000;105(11):1521–1523. https://doi.org/10.1172/JCI10230.
© 2000 The American Society for Clinical Investigation
Serotonin (5-hydroxytryptamine; 5-HT) is one of many vasoactive substances postulated to participate in the development of hypoxia-induced pulmonary hypertension. Pulmonary vasoactive responses to hypoxia are intensified by 5-HT (1), but attempts to block hypoxia-induced pulmonary hypertension with 5-HT receptor antagonists have met with mixed success. Furthermore, it has been difficult to establish a causal relationship between 5-HT and the physiological response to hypoxia. Lacking in much of this work is a clear distinction between two classes of molecules, 5-HT transporters and 5-HT receptors, either or both of which may participate in the response of pulmonary vascular smooth muscle cells to 5-HT.
High levels of 5-HT have been associated with pulmonary hypertension in several systems. Herve et al. (2) described a patient with pulmonary hypertension who had high levels of circulating 5-HT due to a platelet storage disease, and other individuals have been described with primary pulmonary hypertension associated with elevated serum 5-HT levels (3). In the fawn-hooded rat, an animal model for platelet storage disease that exhibits high circulating levels of 5-HT, mild hypoxia also leads to pulmonary hypertension (4, 5). Finally, pulmonary hypertension is also associated with appetite suppressants, such as fenfluramine or dexfenfluramine, which block reuptake of 5-HT.
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Transduction of 5-HT signals through the serotonin transporter and the 5-HT receptors
Several subtypes of signal-transducing 5-HT receptors have been characterized pharmacologically and cloned (see review in ref. 6). Depending on their subtype, these receptors may act on G-proteins and thereby activate phospholipase C or adenylate cyclase (6). By analogy with other signaling molecules, it is generally assumed that these receptors operate at the cell surface, without necessarily mediating the uptake of 5-HT. In addition, 5-HT may be internalized into a variety of cell types, including platelets, neurons, mast cells, endothelial cells, and smooth muscle cells, through an active transport mechanism that is powered by a transmembrane Na+/Cl– gradient (7). Transporter genes have been cloned in rat, human, mouse, bovine, and Drosophilia (8–13). The serotonin transporter (SERT) belongs to a large family of sodium chloride–dependent γ-aminobutyric acid/norepinephrine transporters. The precise relationship between 5-HT receptors and the transporter has never been adequately defined. Some cells appear to contain receptors, others transporters, and some both.
Both bovine pulmonary artery endothelial and smooth muscle cells actively transport 5-HT (14, 15), and this transport is enhanced by exposure of cells to hypoxia (15, 16). Hypoxia also activates the mitogen-activated protein (MAP) kinase (17), thereby inducing c-fos transcription, which leads to activation of hypoxia-inducible factor-1 (HIF-1) (18). In the bovine pulmonary artery smooth muscle cell, only one 5-HT receptor has been identified, which resembles the 5-HT1A or 5-HT4 receptor (19, 20). Stimulation of this receptor in the presence of a phosphodiesterase inhibitor elevates cAMP and inhibits cellular proliferation (21). On the other hand, in the absence of phosphodiesterase inhibition, cellular cAMP does not rise, and 5-HT transport predominates over transmembrane signaling, resulting in cellular proliferation and hypertrophy at concentrations of 5-HT in the micromolar range (22). Monoamine oxidase inhibitors, which block the intracellular degradation of 5-HT, augment this proliferative response. Thus, in this case, it appears that the intracellular accumulation of 5-HT drives the proliferative process, since it is doubtful that monoamine oxidase affects 5-HT metabolism at the cell surface.
5-HT signaling through SERT also acts through a variety of other signaling molecules — tyrosine phosphorylation of GTPase-activating protein, Ras activation, activation of NAD(P)H oxidase to produce reactive oxygen species (ROSs), and activation of ERK1/ERK2 (extracellular signal-regulated kinase-1/-2) MAP kinase — to induce smooth muscle cell hyperplasia or hypertrophy (Figure 1) (23–25). These signals occur only in intact cells, not in cellular homogenates (23). Although bovine pulmonary artery endothelial cells actively transport 5-HT, they neither proliferate nor induce protein tyrosine phosphorylation in response to this stimulus (23). We previously demonstrated that Chinese hamster lung fibroblasts respond to 5-HT through both SERT and a 5-HT2 receptor, leading to both transmembrane signaling and proliferation (25). Similarly, in rat mesangial cells, 5-HT activates a 5-HT2A receptor through a Gq-protein–coupled pathway, leading to activation of phospholipase C, NAD(P)H oxidase, and ERK MAP kinase (26, 27).
Figure 1Stimulation begins with contact between 5-HT and either a transporter or receptor, which may lead to activation of Ras or Rac or both. The signal then activates a NAD(P)H oxidase that has not been fully characterized, leading to release of reactive oxygen species (ROS) and the activation of the ERK1 or ERK2 MAP kinases. The consequent changes in gene expression culminate in both cellular hyperplasia and hypertrophy.
In Chinese ovary fibroblasts expressing an exogenous 5-HT1A receptor, 5-HT also activates NAD(P)H oxidase, ROS formation, and the ERK MAP kinase through a Gi-protein–mediated pathway (28). Humblot et al. reported that, in PC12 cells, 5-HT induces tyrosine phosphorylation and subsequently activates TIS8/egr-1 and c-fos expression (29). Furthermore, Nebigil and colleagues recently showed that the 5-HT2B receptor stimulates cyclin-dependent kinase activities by at least two mechanisms: it acts through c-Src and the receptor tyrosine kinase platelet-derived growth factor receptor (PDGFR) to stimulate cyclin D1/cdk4 activity, and it acts through c-Src alone to stimulate cyclin E/cdk2 (30). However, since SERT and 5-HT receptors may coexist in a single cell type, it remains possible that some of these effects require SERT rather than the 5-HT receptor. Nevertheless, it appears that activation of either SERT or receptor by 5-HT, depending upon cell type, can initiate a signaling process that activates cell proliferation (Figure 1).
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