This Article Full Text Full Text (PDF) All Versions of this Article: 49/1/232    most recent 01.HYP.0000252210.58849.78v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Morecroft, I. Articles by MacLean, M. R. Search for Related Content PubMed PubMed Citation Articles by Morecroft, I. Articles by MacLean, M. R. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Medline Plus Health Information Pulmonary Hypertension Related Collections Animal models of human disease Pulmonary circulation and disease Other Vascular biology

(Hypertension. 2007;49:232.)
© 2007 American Heart Association, Inc.

Original Articles

Effect of Tryptophan Hydroxylase 1 Deficiency on the Development of Hypoxia-Induced Pulmonary Hypertension

Ian Morecroft; Yvonne Dempsie; Michael Bader; Diego J. Walther; Katarina Kotnik; Lynn Loughlin; Margaret Nilsen; Margaret R. MacLean

From the Division of Neuroscience and Biomedical Systems (I.M., Y.D., L.L., M.N., M.R.M.), Faculty of Biomedical and Life Sciences, Glasgow University, Glasgow, Scotland; and the Max-Delbrück-Center for Molecular Medicine (M.B., D.J.W., K.K.), Berlin, Germany.

Correspondence to Margaret R. MacLean, Room 417, West Medical Building, Glasgow University, G12 8QQ, Scotland. E-mail m.maclean{at}bio.gla.ac.uk

Tryptophan hydroxylase 1 catalyzes the rate-limiting step in the synthesis of serotonin in the periphery. Recently, it has been shown that expression of the tryptophan hydroxylase 1 gene is increased in lungs and pulmonary endothelial cells from patients with idiopathic pulmonary arterial hypertension. Here we investigated the effect of genetic deletion of tryptophan hydroxylase 1 on hypoxia-induced pulmonary arterial hypertension in mice by measuring pulmonary hemodynamics and pulmonary vascular remodeling before and after 2 weeks of hypoxia. In wild-type mice, hypoxia increased right ventricular pressure and pulmonary vascular remodeling. These effects of hypoxia were attenuated in the tryptophan hydroxylase 1–/–mice. Hypoxia increased right ventricular hypertrophy in both wild-type and tryptophan hydroxylase 1–/–mice suggesting that in vivo peripheral serotonin has a differential effect on the pulmonary vasculature and right ventricular hypertrophy. Contractile responses to serotonin were increased in pulmonary arteries from tryptophan hydroxylase 1–/–mice. Hypoxia increased serotonin-mediated contraction in vessels from the wild-type mice, but this was not further increased by hypoxia in the tryptophan hydroxylase 1–/–mice. In conclusion, these results indicate that tryptophan hydroxylase 1 and peripheral serotonin play an essential role in the development of hypoxia-induced elevations in pulmonary pressures and hypoxia-induced pulmonary vascular remodeling. In addition, the results suggest that, in mice, serotonin has differential effects on the pulmonary vasculature and right ventricular hypertrophy.

Key Words: pulmonary circulation • serotonin • hypoxia • transgenic animals

This article has been cited by other articles:

				L. Kugathasan, J. B. Ray, Y. Deng, E. Rezaei, D. J. Dumont, and D. J. Stewart The angiopietin-1-Tie2 pathway prevents rather than promotes pulmonary arterial hypertension in transgenic mice J. Exp. Med., September 28, 2009; 206(10): 2221 - 2234. [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]

				N. W. Morrell, S. Adnot, S. L. Archer, J. Dupuis, P. Lloyd Jones, M. R. MacLean, I. F. McMurtry, K. R. Stenmark, P. A. Thistlethwaite, N. Weissmann, et al. Cellular and molecular basis of pulmonary arterial hypertension. J. Am. Coll. Cardiol., June 30, 2009; 54(1 Suppl): S20 - S31. [Abstract] [Full Text] [PDF]

				N. Alenina, D. Kikic, M. Todiras, V. Mosienko, F. Qadri, R. Plehm, P. Boye, L. Vilianovitch, R. Sohr, K. Tenner, et al. Growth retardation and altered autonomic control in mice lacking brain serotonin PNAS, June 23, 2009; 106(25): 10332 - 10337. [Abstract] [Full Text] [PDF]

				Y. Dempsie, I. Morecroft, D. J. Welsh, N. A. MacRitchie, N. Herold, L. Loughlin, M. Nilsen, A. J. Peacock, A. Harmar, M. Bader, et al. Converging Evidence in Support of the Serotonin Hypothesis of Dexfenfluramine-Induced Pulmonary Hypertension With Novel Transgenic Mice Circulation, June 3, 2008; 117(22): 2928 - 2937. [Abstract] [Full Text] [PDF]

				E. K. Weir, M. Obreztchikova, and Z. Hong Fenfluramine: riddle or Rosetta stone? Eur. Respir. J., February 1, 2008; 31(2): 232 - 235. [Full Text] [PDF]

				M. Xu, O. Platoshyn, A. Makino, W. H. Dillmann, K. Akassoglou, C. V. Remillard, and J. X.-J. Yuan Characterization of agonist-induced vasoconstriction in mouse pulmonary artery Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H220 - H228. [Abstract] [Full Text] [PDF]

				A. E. Linder, W. Ni, J. L. Diaz, T. Szasz, R. Burnett, and S. W. Watts Serotonin (5-HT) in Veins: Not All in Vain J. Pharmacol. Exp. Ther., November 1, 2007; 323(2): 415 - 421. [Abstract] [Full Text] [PDF]