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(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

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