Circulation Research. 2004
Published online before print April 1, 2004, doi: 10.1161/01.RES.0000126847.27660.69
Published online before print April 1, 2004, doi: 10.1161/01.RES.0000126847.27660.69
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Submitted on August 6, 2003
Revised on March 16, 2004
Accepted on March 16, 2004
Serotonin-Induced Smooth Muscle Hyperplasia in Various Forms of Human Pulmonary Hypertension
Elisabeth Marcos ;
From INSERM U492 and Service de Physiologie Explorations Fonctionnelles (E.M., O.S., S.A., S.E.), Hôpital H. Mondor, Créteil, France; UPRES EA2705 (E.F., P.D.), Service de Pneumologie, Hôpital A. Béclère, Paris, France; UPRES EA2705 (M.H., G.S.), Service de Chirurgie Thoracique, Vasculaire et de Transplantation Cardiopulmonaire, Hôpital Marie Lannelongue, Paris, France; and INSERM U288 (M.H.), NeuroPsychoPharmacologie Moléculaire, Cellulaire et Fonctionnelle, Faculté de Médecine Pitié-Salpêtrière, Paris, France.
* To whom correspondence should be addressed. E-mail: eddahibi{at}im3.inserm.fr.
Hyperplasia of pulmonary artery smooth muscle cells (PA-SMCs) is a hallmark pathological feature of pulmonary hypertension (PH). Serotonin (5-HT) is involved in the hyperplasia through its interactions with specific receptors and internalization by a specific plasma membrane transporter. We investigated the expression and role of the 5-HT transporter (5-HTT) and 5-HT1B, 5-HT2A, and 5-HT2B receptors in lungs and isolated PA-SMCs from patients with primary PH (n=14), pulmonary veno-occlusive disease (n=4), or secondary PH (SPH, n=8) and nonpulmonary hypertensive control subjects. Whereas strong immunostaining for the three receptor types and 5-HTT was seen in remodeled pulmonary vessels from patients in all PH categories, only 5-HTT expression was increased in lungs and cultured PA-SMCs from patients versus controls. The increased growth response of PA-SMCs from patients with primary PH, pulmonary veno-occlusive disease, or SPH to 5-HT or serum was entirely attributable to 5-HTT overexpression, because 5-HTT inhibitors but not 5-HT receptor antagonists abolished 5-HT mitogenic activity and reduced the serum-induced growth response to similar levels in patients as in controls. The L-allelic variant of the 5-HTT gene promoter, which is associated with 5-HTT overexpression, was present homozygously in 14 of 25 (56%) lung transplantation patients with SPH but in only 27% of controls. Polymorphism of the 5-HTT gene promoter was only partly responsible for the increased 5-HTT expression in PH, because PA-SMCs from patients exhibited higher 5-HTT levels than same-genotype cells from controls and no additional promoter sequence alterations were found. We conclude that 5-HTT overexpression is a common pathogenic mechanism in various forms of PH.
Key words: human pulmonary hypertension • serotonin transporter • serotonin receptors • pulmonary artery smooth muscle cells
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