Skip to main content
SpringerLink
Log in
Book cover

Membrane Receptors, Channels and Transporters in Pulmonary Circulation pp 309–322Cite as

The Serotonin Hypothesis of Pulmonary Hypertension Revisited

  • Conference paper
  • First Online:

Part of the book series: Advances in Experimental Medicine and Biology ((volume 661))

Abstract

The serotonin hypothesis of pulmonary arterial hypertension (PAH) arose after an outbreak of PAH in patients taking the anorexigenic drugs aminorex and dexfenfluramine. Both of these drugs are serotonin transporter (SERT) substrates and indirect serotinergic agonists. There is now a wealth of evidence to support a role for serotonin in the pathobiology of PAH. Synthesis of serotonin can occur in pulmonary artery endothelial cells by the enzyme tryptophan hydroxylase 1 (TPH1). Serotonin then acts at the 5-HT1B receptor and the SERT to mediate constriction and proliferation of pulmonary artery smooth muscle cells. Downstream signalling molecules which play a role in serotonin-induced constriction and proliferation include reactive oxygen species (ROS), Rho-kinase (ROCK) p38 and extracellular signal-regulated kinase (ERK). There is also evidence to suggest that serotonin may interact with the bone morphogenetic receptor type II (BMPRII) to provide a ‘second hit’ risk factor for PAH.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Simonneau G, Galiè N, Rubin LJ et al (2004) Clinical classification of pulmonary hypertension. J Am Coll Cardiol 43:5S-12S

    Article  PubMed  Google Scholar 

  2. Rothman RB, Ayestas MA, Dersch CM, Baumann MH (1999) Aminorex, fenfluramine, and chlorphentermine are serotonin transporter substrates - implications for primary pulmonary hypertension. Circulation 100:869-875

    Article  PubMed  CAS  Google Scholar 

  3. Ulus IH, Maher TJ, Wurtman RJ (2000) Characterization of phentermine and related compounds as monoamine oxidase (MAO) inhibitors. Biochem Pharmacol 59:1611-1621

    Article  PubMed  CAS  Google Scholar 

  4. Hervé P, Launay JM, Scrobohaci ML et al (1995) Increased plasma serotonin in primary pulmonary hypertension. Am J Med 99:249-254

    Article  PubMed  Google Scholar 

  5. Herve P, Drouet L, Dosquet C et al (1990) Primary pulmonary hypertension in a patient with a familial platelet storage pool disease: role of serotonin. Am J Med 89:117-120

    Article  PubMed  CAS  Google Scholar 

  6. Martin F, Artigas F (1992) Simultaneous effects of para-chloroamphetamine, D-fenfluramine, and reserpine on free and stored 5-hydroxytryptamine in brain and blood. J Neurochem 59:1138-1144

    Article  PubMed  CAS  Google Scholar 

  7. Zolkowska D, Baumann MH, Rothman RB (2008) Chronic fenfluramine administration increases plasma serotonin (5-hydroxytryptamine) to nontoxic levels. J Pharmacol Exp Ther 324:791-797

    Article  PubMed  CAS  Google Scholar 

  8. Lee SL, Wang WW, Fanburg BL (2001) Dexfenfluramine as a mitogen signal via the formation of superoxide anion. FASEB J 15:1324-1325

    PubMed  CAS  Google Scholar 

  9. Patnaude LA, Undem BJ, O’Rourke ST (2000) Dexfenfluramine-induced contraction of human and rat isolated pulmonary arteries. Eur J Pharmacol 401:229-234

    Article  PubMed  CAS  Google Scholar 

  10. Reeve HL, Archer SL, Soper M, Weir EK (1999) Dexfenfluramine increases pulmonary smooth muscle intracellular Ca2+ independent of membrane potential. Am J Physiol Lung Cell Mol Physiol 277:L662-L666

    CAS  Google Scholar 

  11. Weir EK, Reeve HL, Huang JMC, Michelakis E, Nelson DP, Hampl V et al (1996) Anorexic agents aminorex, fenfluramine, and dexfenfluramine inhibit potassium current in rat pulmonary vascular smooth muscle and cause pulmonary vasoconstriction. Circulation 94:2216-2220

    Article  PubMed  CAS  Google Scholar 

  12. Rothman RB, Baumann MH (2002) Therapeutic and adverse actions of serotonin transporter substrates. Pharmacol Ther 95:73-88

    Article  PubMed  CAS  Google Scholar 

  13. Alexander SPH, Mathie A, Peters JA (2005) Guide to receptors and channels, 1st edition (2005 revision). Br J Pharmacol 144:S1-S128

    Article  PubMed  Google Scholar 

  14. Frishman WH, Huberfeld S, Okin S, Wang YH, Kumar A, Shareef B (1995) Serotonin and serotonin antagonism in cardiovascular and non-cardiovascular disease. J Clin Pharmacol 35:541-572

    PubMed  CAS  Google Scholar 

  15. McGoon MD, Vlietstra RE (1987) Acute hemodynamic response to the S2-serotonergic receptor antagonist, ketanserin, in patients with primary pulmonary hypertension. Int J Cardiol 14:303-309

    Article  PubMed  CAS  Google Scholar 

  16. MacIntyre PD, Bhargava B, Hogg KJ, Gemmill JD, Hillis WS (1993) Effect of subcutaneous sumatriptan, a selective 5Ht1 agonist, on the systemic, pulmonary, and coronary circulation. Circulation 87:401-405

    Article  PubMed  CAS  Google Scholar 

  17. MacLean MR, Clayton RA, Templeton AGB, Morecroft I (1996) Evidence for 5-HT1-like receptor-mediated vasoconstriction in human pulmonary artery. Br J Pharmacol 119:277-282

    Article  PubMed  CAS  Google Scholar 

  18. Morecroft I, Heeley RP, Prentice HM, Kirk A (1999) MacLean MR. 5-hydroxytryptamine receptors mediating contraction in human small muscular pulmonary arteries: importance of the 5-HT1B receptor. Br J Pharmacol 128:730-734

    Article  PubMed  CAS  Google Scholar 

  19. Launay JM, Herve P, Peoc’h K et al (2002) Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension. Nat Med 8:1129-1135

    Article  PubMed  CAS  Google Scholar 

  20. MacLean MR (1999) Pulmonary hypertension, anorexigens and 5-HT: pharmacological synergism in action? Trends Pharmacol Sci 20:490-495

    Article  PubMed  CAS  Google Scholar 

  21. Keegan A, Morecroft I, Smillie D, Hicks MN, MacLean MR (2001) Contribution of the 5-HT1B receptor to hypoxia-induced pulmonary hypertension - converging evidence using 5-HT1B-receptor knockout mice and the 5-HT1B/1D-receptor antagonist GR127935. Circ Res 89:1231-1239

    Article  PubMed  CAS  Google Scholar 

  22. Rondelet B, Van Beneden R, Kerbaul F et al (2003) Expression of the serotonin 1b receptor in experimental pulmonary hypertension. Eur Respir J 22:408-412

    Article  PubMed  CAS  Google Scholar 

  23. Lawrie A, Spiekerkoetter E, Martinez EC et al (2005) Interdependent serotonin transporter and receptor pathways regulate S100A4/Mts1, a gene associated with pulmonary vascular disease. Circ Res 97:227-235

    Article  PubMed  CAS  Google Scholar 

  24. Kasparian A, Floros A, Gialafos E et al (2007) Raynaud’s phenomenon is correlated with elevated systolic pulmonary arterial pressure in patients with systemic lupus erythematosus. Lupus 16:505-508

    Article  PubMed  CAS  Google Scholar 

  25. Bailey SR, Elliott J (1998) Evidence for different 5-HT1B/1D receptors mediating vasoconstriction of equine digital arteries and veins. Eur J Pharmacol 355:175-187

    Article  PubMed  CAS  Google Scholar 

  26. Susol E, MacGregor AJ, Barrett JH et al (2000) A two-stage, genome-wide screen for susceptibility loci in primary Raynaud’s phenomenon. Arthritis Rheum 43:1641-1646

    Article  PubMed  CAS  Google Scholar 

  27. Bernatsky S, Pineau CA, Lee JL, Clarke AE (2006) Headache, Raynaud’s syndrome and serotonin receptor agonists in systemic lupus erythematosus. Lupus 15:671-674

    Article  PubMed  CAS  Google Scholar 

  28. Cogolludo A, Moreno L, Lodi F et al (2006) 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 98:931-938

    Article  PubMed  CAS  Google Scholar 

  29. Welsh DJ, Harnett M, Maclean M, Peacock AJ (2004) Proliferation and signaling in fibroblasts - role of 5-hydroxytryptamine2A receptor and transporter. Am J Respir Crit Care Med 170:252-259

    Article  PubMed  Google Scholar 

  30. Callebert J, Esteve JM, Hervé P et al (2006) Evidence for a control of plasma serotonin levels by 5-hydroxytryptamine2B receptors in mice. J Pharmacol Exp Ther 317:724-731

    Article  PubMed  CAS  Google Scholar 

  31. Blanpain C, Le Poul E, Parma J, Knoop C, Detheux M, Parmentier M et al (2003) Serotonin 5-HT2B receptor loss of function mutation in a patient with fenfluramine-associated primary pulmonary hypertension. Cardiovasc Res 60:518-528

    Article  PubMed  CAS  Google Scholar 

  32. Torres GE, Gainetdinov RR, Caron MG (2003) Plasma membrane monoamine transporters: structure, regulation and function. Nat Rev Neurosci 4:13-25

    Article  PubMed  CAS  Google Scholar 

  33. Eddahibi S, Humbert M, Fadel E et al (2001) Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. J Clin Invest 108:1141-1150

    PubMed  CAS  Google Scholar 

  34. Eddahibi S, Chaouat A, Morrell N et al (2003) Polymorphism of the serotonin transporter gene and pulmonary hypertension in chronic obstructive pulmonary disease. Circulation 108:1839-1844

    Article  PubMed  CAS  Google Scholar 

  35. Long L, Aldashev AA, Hensiek A et al (2002) Preliminary identification of genetic loci associated with high altitude pulmonary hypertension by association mapping. Thorax 57:S110

    Article  Google Scholar 

  36. Olson TP, Snyder EM, Frantz RP, Turner ST, Johnson BD (2007) Repeat length polymorphism of the serotonin transporter gene influences pulmonary artery pressure in heart failure. Am Heart J 153:426-432

    Article  PubMed  CAS  Google Scholar 

  37. Machado RD, Koehler R, Glissmeyer E et al (2006) Genetic association of the serotonin transporter in pulmonary arterial hypertension. Am J Respir Crit Care Med 173:793-797

    Article  PubMed  CAS  Google Scholar 

  38. Willers ED, Newman JH, Loyd JE et al (2006) Serotonin transporter polymorphisms in familial and idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 173:798-802

    Article  PubMed  CAS  Google Scholar 

  39. Eddahibi S, Hanoun N, Lanfumey L et al (2000) Attenuated hypoxic pulmonary hypertension in mice lacking the 5-hydroxytryptamine transporter gene. J Clin Invest 105:1555-1562

    Article  PubMed  CAS  Google Scholar 

  40. MacLean MR, Deuchar GA, Hicks MN et al (2004) Overexpression of the 5-hydroxytryptamine transporter gene - effect on pulmonary hemodynamics and hypoxia-induced pulmonary hypertension. Circulation 109:2150-2155

    Article  PubMed  CAS  Google Scholar 

  41. Guignabert C, Izikki M, Tu LI et al (2006) Transgenic mice overexpressing the 5-hydroxytryptamine transporter gene in smooth muscle develop pulmonary hypertension. Circ Res 98:1323-1330

    Article  PubMed  CAS  Google Scholar 

  42. Morecroft I, Loughlin L, Nilsen M et al (2005) Functional interactions between 5-hydroxytryptamine receptors and the serotonin transporter in pulmonary arteries. J Pharmacol Exp Ther 313:539-548

    Article  PubMed  CAS  Google Scholar 

  43. Sato K, Webb S, Tucker A et al (1992) Factors influencing the idiopathic development of pulmonary hHypertension in the fawn hooded rat. Am Rev Respir Dis 145:793-797

    PubMed  CAS  Google Scholar 

  44. Marcos E, Adnot S, Pham MH et al (2003) Serotonin transporter inhibitors protect against hypoxic pulmonary hypertension. Am J Respir Crit Care Med 168:487-493

    Article  PubMed  Google Scholar 

  45. Guignabert C, Raffestin B, Benferhat R et al (2005) Serotonin transporter inhibition prevents and reverses monocrotaline-induced pulmonary hypertension in rats. Circulation 111:2812-2819

    Article  PubMed  CAS  Google Scholar 

  46. Laudi S, Trump S, Schmitz V et al (2007) Serotonin transporter protein in pulmonary hypertensive rats treated with atorvastatin. Am J Physiol Lung Cell Mol Physiol 293:L630-L6L8

    Article  PubMed  CAS  Google Scholar 

  47. Marcos E, Fadel E, Sanchez O et al (2004) Serotonin-induced smooth muscle hyperplasia in various forms of human pulmonary hypertension. Circ Res 94:1263-1270

    Article  PubMed  CAS  Google Scholar 

  48. Lee SL, Wang WW, Lanzillo JJ, Fanburg BL (1994) Serotonin produces both hyperplasia and hypertrophy of bovine pulmonary artery smooth muscle cells in culture. Am J Physiol 266:L46-L52

    PubMed  CAS  Google Scholar 

  49. Liu YL, Suzuki YJ, Day RM, Fanburg BL (2004) Rho kinase-induced nuclear translocation of ERK1/ERK2 in smooth muscle cell mitogenesis caused by serotonin. Circ Res 95:579-586

    Article  PubMed  CAS  Google Scholar 

  50. Dempsie Y, Morecroft I, Welsh DJ et al (2008) Converging evidence in support of the serotonin hypothesis of dexfenfluramine-induced pulmonary hypertension with novel transgenic mice. Circulation 117:2928-2937

    Article  PubMed  CAS  Google Scholar 

  51. Walther DJ, Bader M (2003) A unique central tryptophan hydroxylase isoform. Biochem Pharmacol 66:1673-1680

    Article  PubMed  CAS  Google Scholar 

  52. Eddahibi S, Guignabert C, Barlier-Mur AM et al (2006) Cross talk between endothelial and smooth muscle cells in pulmonary hypertension - critical role for serotonin-induced smooth muscle hyperplasia. Circulation 113:1857-1864

    Article  PubMed  CAS  Google Scholar 

  53. Morecroft I, Dempsie Y, Bader M et al (2007) Effect of tryptophan hydroxylase 1 deficiency on the development of hypoxia-induced pulmonary hypertension. Hypertension 49:232-236

    Article  PubMed  CAS  Google Scholar 

  54. Lee SL, Wang WW, Finlay GA, Fanburg BL (1999) Serotonin stimulates mitogen-activated protein kinase activity through the formation of superoxide anion. Am J Physiol Lung Cell Mol Physiol 277:L282-L291

    CAS  Google Scholar 

  55. Suzuki YJ, Day RM, Tan CC et al (2003) Activation of GATA-4 by serotonin in pulmonary artery smooth muscle cells. J Biol Chem 278:17525-17531

    Article  PubMed  CAS  Google Scholar 

  56. Lee SL, Wang WW, Fanburg BL (1998) Superoxide as an intermediate signal for serotonin-induced mitogenesis. Free Radic Biol Med 24:855-858

    Article  PubMed  Google Scholar 

  57. Liu JQ, Folz RJ (2004) Extracellular superoxide enhances 5-HT-induced murine pulmonary artery vasoconstriction. Am J Physiol Lung Cell Mol Physiol 287:L111-L118

    Article  PubMed  CAS  Google Scholar 

  58. Mair KM, MacLean MR, Morecroft I, Dempsie Y, Palmer TM (2008) Novel interactions between the 5-HT transporter, 5-HT1B receptors and Rho kinase in vivo and in pulmonary fibroblasts. Br J Pharmacol 155:606-616

    Article  PubMed  CAS  Google Scholar 

  59. Guilluy C, Rolli-Derkinderen M, Tharaux PL, Melino G, Pacaud P, Loirand G (2007) Transglutaminase-dependent RhoA activation and depletion by serotonin in vascular smooth muscle cells. J Biol Chem 282:2918-2928

    Article  PubMed  CAS  Google Scholar 

  60. Walther DJ, Peter JU, Winter S et al (2003) Serotonylation of small GTPases is a signal transduction pathway that triggers platelet alpha-granule release. Cell 115:851-862

    Article  PubMed  CAS  Google Scholar 

  61. Das M, Bouchey DM, Moore MJ, Hopkins DC, Nemenoff RA, Stenmark KR (2001) Hypoxia-induced proliferative response of vascular adventitial fibroblasts is dependent on G protein-mediated activation of mitogen-activated protein kinases. J Biol Chem 276:15631-15640

    Article  PubMed  CAS  Google Scholar 

  62. Mortimer HJ, Peacock AJ, Kirk A, Welsh DJ P38 MAP (2007) kinase: essential role in hypoxia-mediated human pulmonary artery fibroblast proliferation. Pulm Pharmacol Ther 20:718-725

    Article  PubMed  CAS  Google Scholar 

  63. Mitani Y, Mutlu A, Russell JC, Brindley DN, DeAlmeida J, Rabinovitch M (2002) Dexfenfluramine protects against pulmonary hypertension in rats. J Appl Physiol 93:1770-1778

    PubMed  CAS  Google Scholar 

  64. Rochefort GY, Lemaire MC, Eder V et al (2006) Dexfenfluramine does not worsen but moderates progression of chronic hypoxia-induced pulmonary hypertension. Eur J Pharmacol 550:149-154

    Article  PubMed  CAS  Google Scholar 

  65. Massagué J (2003) Integration of Smad and MAPK pathways: a link and a linker revisited. Genes Dev 17:2993-2997

    Article  PubMed  Google Scholar 

  66. Yang XD, Long L, Southwood M et al (2005) Dysfunctional Smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension. Circ Res 96:1053-1063

    Article  PubMed  CAS  Google Scholar 

  67. Long L, MacLean MR, Jeffery TK et al (2006) Serotonin increases susceptibility to pulmonary hypertension in BMPR2-deficient mice. Circ Res 98:818-827

    Article  PubMed  CAS  Google Scholar 

  68. Morecroft I, Pang L, Baranowska M et al (2009) In vivo effects of a combined 5-HT1B receptor/SERT antagonist in experimental pulmonary hypertension. Cardiovasc Res In press.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Integrative and Systems Biology, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, Scotland, UK

    Margaret R. MacLean & Yvonne Dempsie

Authors
  1. Margaret R. MacLean
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yvonne Dempsie
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Margaret R. MacLean .

Editor information

Editors and Affiliations

  1. Departments of Medicine and Pharmacology, University of Illinois at Chicago, Chicago, 60612, USA

    Jason X. -J. Yuan

  2. Guy’s Hospital Campus, Dept. Physiology, King’s College London, London, SE1 1UL, United Kingdom

    Jeremy P. T. Ward

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Humana Press, a part of Springer Science+Business Media, LLC

About this paper

Cite this paper

MacLean, M.R., Dempsie, Y. (2010). The Serotonin Hypothesis of Pulmonary Hypertension Revisited. In: Yuan, JJ., Ward, J. (eds) Membrane Receptors, Channels and Transporters in Pulmonary Circulation. Advances in Experimental Medicine and Biology, vol 661. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-500-2_20

Download citation

Publish with us

Policies and ethics

Search

Navigation