Published online before print April 1, 2004, doi: 10.1161/01.RES.0000126847.27660.69
© 2004 American Heart Association, Inc.
Integrative Physiology |
Serotonin-Induced Smooth Muscle Hyperplasia in Various Forms of Human Pulmonary Hypertension
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.
Correspondence to Saadia Eddahibi, INSERM U492, Faculté de Médecine, 8, avenue Général Sarrail, 94010 Créteil, France. 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
This article has been cited by other articles:
 |
|
 |
|
  L. Dewachter, S. Adnot, C. Guignabert, L. Tu, E. Marcos, E. Fadel, M. Humbert, P. Dartevelle, G. Simonneau, R. Naeije, et al. Bone morphogenetic protein signalling in heritable versus idiopathic pulmonary hypertension Eur. Respir. J., November 1, 2009; 34(5): 1100 - 1110. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Morecroft, L. Pang, M. Baranowska, M. Nilsen, L. Loughlin, Y. Dempsie, C. Millet, and M. R. MacLean In vivo effects of a combined 5-HT1B receptor/SERT antagonist in experimental pulmonary hypertension Cardiovasc Res, September 25, 2009; (2009) cvp306v2. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. A. Ghofrani, R. J. Barst, R. L. Benza, H. C. Champion, K. A. Fagan, F. Grimminger, M. Humbert, G. Simonneau, D. J. Stewart, C. Ventura, et al. Future perspectives for the treatment of pulmonary arterial hypertension. J. Am. Coll. Cardiol., June 30, 2009; 54(1 Suppl): S108 - S117. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Guilluy, S. Eddahibi, C. Agard, C. Guignabert, M. Izikki, L. Tu, L. Savale, M. Humbert, E. Fadel, S. Adnot, et al. RhoA and Rho Kinase Activation in Human Pulmonary Hypertension: Role of 5-HT Signaling Am. J. Respir. Crit. Care Med., June 15, 2009; 179(12): 1151 - 1158. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. McGoon and G. C. Kane Pulmonary Hypertension: Diagnosis and Management Mayo Clin. Proc., February 1, 2009; 84(2): 191 - 207. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Liu and B. L. Fanburg Phospholipase D signaling in serotonin-induced mitogenesis of pulmonary artery smooth muscle cells Am J Physiol Lung Cell Mol Physiol, September 1, 2008; 295(3): L471 - L478. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Fabre, J. Marchal-Somme, S. Marchand-Adam, C. Quesnel, R. Borie, M. Dehoux, C. Ruffie, J. Callebert, J-M. Launay, D. Henin, et al. Modulation of bleomycin-induced lung fibrosis by serotonin receptor antagonists in mice Eur. Respir. J., August 1, 2008; 32(2): 426 - 436. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-J. Lai, S. S. Pullamsetti, E. Dony, N. Weissmann, G. Butrous, G.-A. Banat, H. A. Ghofrani, W. Seeger, F. Grimminger, and R. T. Schermuly Role of the Prostanoid EP4 Receptor in Iloprost-mediated Vasodilatation in Pulmonary Hypertension Am. J. Respir. Crit. Care Med., July 15, 2008; 178(2): 188 - 196. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Chin and L. J. Rubin Pulmonary arterial hypertension. J. Am. Coll. Cardiol., April 22, 2008; 51(16): 1527 - 1538. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Archer, M. Gomberg-Maitland, M. L. Maitland, S. Rich, J. G. N. Garcia, and E. K. Weir Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1{alpha}-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension and cancer Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H570 - H578. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Fornaro, D. Li, J. Pan, and J. Belik Prenatal Exposure to Fluoxetine Induces Fetal Pulmonary Hypertension in the Rat Am. J. Respir. Crit. Care Med., November 15, 2007; 176(10): 1035 - 1040. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Izikki, N. Hanoun, E. Marcos, L. Savale, A. M. Barlier-Mur, F. Saurini, S. Eddahibi, M. Hamon, and S. Adnot Tryptophan hydroxylase 1 knockout and tryptophan hydroxylase 2 polymorphism: effects on hypoxic pulmonary hypertension in mice Am J Physiol Lung Cell Mol Physiol, October 1, 2007; 293(4): L1045 - L1052. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Liu, M. Li, R. R. Warburton, N. S. Hill, and B. L. Fanburg The 5-HT transporter transactivates the PDGF{beta} receptor in pulmonary artery smooth muscle cells FASEB J, September 1, 2007; 21(11): 2725 - 2734. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Laudi, S. Trump, V. Schmitz, J. West, I. F. McMurtry, H. Mutlak, U. Christians, J. Weimann, U. Kaisers, and W. Steudel Serotonin transporter protein in pulmonary hypertensive rats treated with atorvastatin Am J Physiol Lung Cell Mol Physiol, September 1, 2007; 293(3): L630 - L638. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. F. Wideman, M. E. Chapman, K. R. Hamal, O. T. Bowen, A. G. Lorenzoni, G. F. Erf, and N. B. Anthony An Inadequate Pulmonary Vascular Capacity and Susceptibility to Pulmonary Arterial Hypertension in Broilers Poult. Sci., May 1, 2007; 86(5): 984 - 998. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. D. Willers and J. H. Newman New Risks for Pulmonary Hypertension: Need for a Large Epidemiologic Study Chest, December 1, 2006; 130(6): 1633 - 1635. [Full Text] [PDF]
|
|
|
|
|
|
K. M. Chin, R. N. Channick, and L. J. Rubin Is Methamphetamine Use Associated With Idiopathic Pulmonary Arterial Hypertension? Chest, December 1, 2006; 130(6): 1657 - 1663. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. V. McLaughlin and M. D. McGoon Pulmonary Arterial Hypertension Circulation, September 26, 2006; 114(13): 1417 - 1431. [Full Text] [PDF]
|
|
|
|
 |
|
 M. de Caestecker Serotonin Signaling in Pulmonary Hypertension Circ. Res., May 26, 2006; 98(10): 1229 - 1231. [Full Text] [PDF]
|
|
|
|
|
|
C. Guignabert, M. Izikki, L. I. Tu, Z. Li, P. Zadigue, A.-M. Barlier-Mur, N. Hanoun, D. Rodman, M. Hamon, S. Adnot, et al. Transgenic Mice Overexpressing the 5-Hydroxytryptamine Transporter Gene in Smooth Muscle Develop Pulmonary Hypertension Circ. Res., May 26, 2006; 98(10): 1323 - 1330. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Eddahibi, C. Guignabert, A.-M. Barlier-Mur, L. Dewachter, E. Fadel, P. Dartevelle, M. Humbert, G. Simonneau, N. Hanoun, F. Saurini, et al. Cross Talk Between Endothelial and Smooth Muscle Cells in Pulmonary Hypertension: Critical Role for Serotonin-Induced Smooth Muscle Hyperplasia Circulation, April 18, 2006; 113(15): 1857 - 1864. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Cogolludo, L. Moreno, F. Lodi, G. Frazziano, L. Cobeno, J. Tamargo, and F. Perez-Vizcaino Serotonin Inhibits Voltage-Gated K+ Currents in Pulmonary Artery Smooth Muscle Cells: Role of 5-HT2A Receptors, Caveolin-1, and KV1.5 Channel Internalization Circ. Res., April 14, 2006; 98(7): 931 - 938. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Lesurtel, R. Graf, B. Aleil, D. J. Walther, Y. Tian, W. Jochum, C. Gachet, M. Bader, and P.-A. Clavien Platelet-derived serotonin mediates liver regeneration. Science, April 7, 2006; 312(5770): 104 - 107. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Eddahibi and S. Adnot From functional to genetic studies of a candidate gene for pulmonary hypertension: any point? Am. J. Respir. Crit. Care Med., April 1, 2006; 173(7): 693 - 694. [Full Text] [PDF]
|
|
|
|
|
|
E. D. Willers, J. H. Newman, J. E. Loyd, I. M. Robbins, L. A. Wheeler, M. A. Prince, K. C. Stanton, J. A. Cogan, J. R. Runo, D. Byrne, et al. Serotonin Transporter Polymorphisms in Familial and Idiopathic Pulmonary Arterial Hypertension Am. J. Respir. Crit. Care Med., April 1, 2006; 173(7): 798 - 802. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Liu and B. L. Fanburg Serotonin-Induced Growth of Pulmonary Artery Smooth Muscle Requires Activation of Phosphatidylinositol 3-Kinase/Serine-Threonine Protein Kinase B/Mammalian Target of Rapamycin/p70 Ribosomal S6 Kinase 1 Am. J. Respir. Cell Mol. Biol., February 1, 2006; 34(2): 182 - 191. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Marcos, E. Fadel, O. Sanchez, M. Humbert, P. Dartevelle, G. Simonneau, M. Hamon, S. Adnot, and S. Eddahibi Serotonin Transporter and Receptors in Various Forms of Human Pulmonary Hypertension Chest, December 1, 2005; 128(6_suppl): 552S - 553S. [Full Text] [PDF]
|
|
|
|
|
|
E. Marcos, E. Fadel, O. Sanchez, M. Humbert, P. Dartevelle, G. Simonneau, M. Hamon, S. Adnot, and S. Eddahibi Serotonin Transporter and Receptors in Various Forms of Human Pulmonary Hypertension Chest, December 1, 2005; 128(6_suppl): 552S - 553S. [Full Text] [PDF]
|
|
|
|
|
|
A. Lawrie, E. Spiekerkoetter, E. C. Martinez, N. Ambartsumian, W. J. Sheward, M. R. MacLean, A. J. Harmar, A.-M. Schmidt, E. Lukanidin, and M. Rabinovitch Interdependent Serotonin Transporter and Receptor Pathways Regulate S100A4/Mts1, a Gene Associated With Pulmonary Vascular Disease Circ. Res., August 5, 2005; 97(3): 227 - 235. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Guignabert, B. Raffestin, R. Benferhat, W. Raoul, P. Zadigue, D. Rideau, M. Hamon, S. Adnot, and S. Eddahibi Serotonin Transporter Inhibition Prevents and Reverses Monocrotaline-Induced Pulmonary Hypertension in Rats Circulation, May 31, 2005; 111(21): 2812 - 2819. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Morecroft, L. Loughlin, M. Nilsen, J. Colston, Y. Dempsie, J. Sheward, A. Harmar, and M. R. MacLean Functional Interactions between 5-Hydroxytryptamine Receptors and the Serotonin Transporter in Pulmonary Arteries J. Pharmacol. Exp. Ther., May 1, 2005; 313(2): 539 - 548. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Naeije and S. Eddahibi Serotonin in Pulmonary Arterial Hypertension Am. J. Respir. Crit. Care Med., August 1, 2004; 170(3): 209 - 210. [Full Text] [PDF]
|
|
|
|
|
|
E. K. Weir, Z. Hong, and A. Varghese The Serotonin Transporter: A Vehicle to Elucidate Pulmonary Hypertension? Circ. Res., May 14, 2004; 94(9): 1152 - 1154. [Full Text] [PDF]
|
|