Pulmonary arterial hypertension is a rare, incurable disease of poor prognosis. The pathobiology of pulmonary arterial hypertension has made progress in recent years, but remains incompletely understood. A variety of abnormalities have been described in all compartments of the pulmonary arterial wall, but which one initiates the disease remains a mystery (1). In this issue of the Journal (pp. 252-259), Welsh and coworkers raise arguments in favor of serotonin, a potent vasoconstrictor and mitogen, acting primarily on pulmonary artery adventitial fibroblasts (2). How does this fit into current pathobiological theories of pulmonary hypertension?
Serotonin has long been suspected to play an important role in the pathogenesis of severe pulmonary hypertension. Serotoninergic appetite suppressant drugs, mainly fenfluramines, have been associated with an increased risk of developing pulmonary arterial hypertension (3). Plasma serotonin is increased in patients with pulmonary arterial hypertension (4). Viral induced overexpression of angiopoietin-1 in rodents induces pulmonary hypertension, and this effect appears to be related to stimulation of pulmonary endothelial cells to produce and secrete serotonin (5).
Welsh and coworkers previously reported that hypoxic pulmonary hypertension in rats is associated with increased proliferation of pulmonary but not mesenteric artery fibroblasts, and that this is related to the activation of the stress-activated mitogenactivated-protein kinase p38 (6). Mitogen-activated protein kinases link transmembrane signaling with nuclear gene induction through the modulation of the phosphorylation of transcriptional factors, including the hypoxia-inducible factor (7). Welsh and coworkers now show hypoxia-induced p38 mitogen-activated protein kinase activation and pulmonary artery fibroblast proliferation may result from the interaction between serotonin and a 5-hydroxytryptamine (5HT)-2A receptor (3). In their study, serotonin and serum induced a pulmonary artery fibroblasts proliferation which was markedly enhanced by chronic hypoxic exposure. The mitogenic effects of serotonin could be blocked by 5HT-2A but not by 5HT-1B/1D or 5HT-2B receptor blockers, and were inhibited by the specific p38 mitogen-activated-protein kinase inhibitor SB203580. Serotonin-induced fibroblast proliferation, however, could also be blocked by the serotonin transporter inhibitor fluoxetine, in an additive manner to the 5HT-2A blocker ketanserin, raising the intriguing possibility of a serotonin receptor-transporter cross-talk. Also, the mitogenic effects of serotonin were not observed in the absence of serum, which makes one wonder about the identity of the indispensable comitogen. Thus pulmonary adventitial proliferative effects of serotonin may be more complex than the single activation of a 5HT-2A/ mitogen-activated protein kinase pathway.
The report by Welsh and coworkers is in keeping with previous studies highlighting the importance of adventitial changes causing progressive vessel narrowing and decreased vasoreactivity in several models of pulmonary hypertension (8). If serotonin is confirmed in targeting adventitial fibroblasts, however, one wonders about the mechanisms of intimal and medial changes typically seen in pulmonary hypertension. These could be related to previously shown activated fibroblast migration into medial and intimal layers of the pulmonary arteriolar wall (8). Hypoxia-induced proliferation of fibroblasts also seems to be associated with hypoxia-inducible factors-related secretion of soluble factors that induce proliferation of adjacent smooth muscle cells (9). The exact nature of the interactions between serotonin, fibroblasts, and endothelial and smooth muscles cells surely deserves further investigation.
It has been generally assumed that the main vascular target of serotonin would be smooth muscle cells. Serotonin induces pulmonary vasoconstriction through the interaction with 5HT-1B receptors, less so with 5HT-2A receptors, which seem to be predominantly involved in systemic vasoconstriction and proliferation (10). Whether serotonin interaction with 5HT-1B or 5HT-2A receptors could directly cause pulmonary vascular smooth muscle proliferation is unclear (10). There has been suggestion that the 5HT-2B receptor could also be involved (11), but the recent report of a loss of function (mutation) of the 5HT-2B receptor in a patient with pulmonary arterial hypertension argues against this theory (12). On the other hand, serotonin may enter pulmonary artery smooth muscle cells through the interaction with a specific transporter, and this results in proliferation (2, 10). Mice lacking the serotonin transporter or treated with serotonin transporter inhibitors are protected against hypoxic pulmonary hypertension (2, 10). Hypoxia-induced pulmonary medial hypertrophy is increased in mice overexpressing the serotonin transporter (13). A strong immunostaining of 5HT-1B, 5HT-2A, and 5HT-2B receptors was recently reported in remodeled pulmonary arteries from patients with various forms of severe pulmonary hypertension, but only the serotonin transporter was found to be overexpressed in pulmonary artery smooth muscle cells (14). Like fibroblasts from chronically hypoxic pulmonary arteries, pulmonary artery smooth muscle cells from patients with pulmonary hypertension grow faster than those of controls when stimulated by serotonin or serum. In pulmonary artery smooth muscles cells, these effects are dose-dependently inhibited by the selective serotonin transporter inhibitors, but not by serotonin 5HT-2A or 5HT-1B/1D receptor antagonists (14).
Altogether, these observations are consistent with major mitogenic effects of interaction between serotonin and its transporter accounting for both smooth muscle cell and fibroblast proliferation in pulmonary hypertension. Welsh and coworkers show that fibroblast proliferation in addition depends on the activation of a 5HT-2A/mitogen-activated protein kinase pathway. Smooth muscle cell proliferation has been shown until now to be predominantly serotonin transporter-dependent.
The report of Welsh and coworkers adds to the growing list of biological abnormalities described in all compartments of pulmonary arterioles from pulmonary hypertensive patients, which include intimal vasoconstrictors-vasodilators imbalance, medial increased expression of the serotonin transporter and decreased expressions of potassium channels, adventitial increased expression of tenascin, inflammation, misguided angiogenesis, and hypercoagulability (1). Most recently, the discovery of mutations in the gene encoding the bone morphogenetic protein receptor 2 (BMPR-2) in patients with familial pulmonary hypertension (15) and the report of an upregulation of angiopoietin-1, which shuts off BMPR-2 in patients with various forms of severe pulmonary hypertension (16), introduced the notion of abnormal angiopoietin-1/BMPR-2 signaling playing a central role in the disease. Angiopoietin-1 increases the amounts of serotonin available to smooth muscle cells and fibroblasts (5). Further studies will have to clarify how abnormal angiopoietin-1/BMPR2 signaling interacts with serotonin and its transporter and receptors.
In the meantime, efficacy of therapies aimed at the restoration of endothelium equilibrium, by the administration of prostacyclins or endothelin receptor blockers (1), continues to suggest that deficient endothelial control of pulmonary vascular smooth muscle cell proliferation is a primary cause of the disease. The report by Welsh and coworkers rather points at a dynamic reciprocity of all vessel layer components, opening new perspectives in research on the still unresolved pathobiology of pulmonary hypertension.
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Conflict of Interest Statement: R.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.E. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
ROBERT NAEIJE, M.D.
Free University of Brussels
SAADIA EDDAHIBI, PH.D.
Faculty of Medicine
Copyright American Thoracic Society Aug 1, 2004
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