© 1999 American Heart Association, Inc.
Original Contribution |
Induction of Serotonin Transporter by Hypoxia in Pulmonary Vascular Smooth Muscle Cells
Relationship With the Mitogenic Action of Serotonin
From the Département de Physiologie (S.E., B.R., S.A.), INSERM U492, Créteil, France, and INSERM U288, NeuroPsychoPharmacologie Moléculaire, Cellulaire et Fonctionnelle (V.F., C.B., M.P.M., M.H.), Faculté de Médecine Pitié-Salpêtrière, Paris, France.
Correspondence to S. Eddahibi, INSERM U492 et Département de Physiologie Centre Hospitalier Universitaire Henri Mondor, 94010 Créteil, France. E-mail eddahibi{at}im3.inserm.fr
Abstract—The increased delivery of serotonin (5-hydroxytryptamine, 5-HT) to the lung aggravates the development of hypoxia-induced pulmonary hypertension in rats, possibly through stimulation of the proliferation of pulmonary artery smooth muscle cells (PA-SMCs). In cultured rat PA-SMCs, 5-HT (10–8 to 10–6 mol/L) induced DNA synthesis and potentiated the mitogenic effect of platelet-derived growth factor-BB (10 ng/mL). This effect was dependent on the 5-HT transporter (5-HTT), since it was prevented by the 5-HTT inhibitors fluoxetine (10–6 mol/L) and paroxetine (10–7 mol/L), but it was unaltered by ketanserin (10–6 mol/L), a 5-HT2A receptor antagonist. In PA-SMCs exposed to hypoxia, the levels of 5-HTT mRNA (measured by competitive reverse transcriptase–polymerase chain reaction) increased by 240% within 2 hours, followed by a 3-fold increase in the uptake of [3H]5-HT at 24 hours. Cotransfection of the cells with a construct of human 5-HTT promoter-luciferase gene reporter and of pCMV-ß-galactosidase gene allowed the demonstration that exposure of cells to hypoxia produced a 5.5-fold increase in luciferase activity, with no change in ß-galactosidase activity. The increased expression of 5-HTT in hypoxic cells was associated with a greater mitogenic response to 5-HT (10–8 to 10–6 mol/L) in the absence as well as in the presence of platelet-derived growth factor-BB. 5-HTT expression assessed by quantitative reverse transcriptase–polymerase chain reaction and in situ hybridization in the lungs was found to predominate in the media of pulmonary artery, in which a marked increase was noted in rats that had been exposed to hypoxia for 15 days. These data show that in vitro and in vivo exposure to hypoxia induces, via a transcriptional mechanism, 5-HTT expression in PA-SMCs, and that this effect contributes to the stimulatory action of 5-HT on PA-SMC proliferation. In vivo expression of 5-HTT by PA-SMC may play a key role in serotonin-mediated pulmonary vascular remodeling.
Key Words: 5-hydroxytryptamine transporter • hypoxia • pulmonary arterial smooth muscle cell • pulmonary hypertension
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