Serotonin-induced smooth muscle hyperplasia in various forms of human pulmonary hypertension.
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.
Marcos
Elisabeth
E
INSERM U492 and Service de Physiologie Explorations Fonctionnelles, Hôpital H. Mondor, Créteil, France.
Fadel
Elie
E
Sanchez
Olivier
O
Humbert
Marc
M
Dartevelle
Philippe
P
Simonneau
Gerald
G
Hamon
Michel
M
Adnot
Serge
S
Eddahibi
Saadia
S
D000293:Adolescent; D000328:Adult; D000483:Alleles; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D002455:Cell Division; D002478:Cells, Cultured / Q000473:pathology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D006965:Hyperplasia; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D007438:Introns / Q000235:genetics; D008171:Lung Diseases / Q000150:complications / Q000473:pathology; D016040:Lung Transplantation; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D011651:Pulmonary Artery / Q000473:pathology*; D011668:Pulmonary Veno-Occlusive Disease / Q000235:genetics / Q000473:pathology / Q000601:surgery; D012333:RNA, Messenger / Q000096:biosynthesis; D011985:Receptors, Serotonin / Q000235:genetics / Q000502:physiology; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins; D017540:Tunica Media / Q000737:chemistry / Q000473:pathology
D002352:Carrier Proteins; D016895:Culture Media, Serum-Free; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D011985:Receptors, Serotonin; C493230:SLC6A4 protein, human; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin