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

Research output: Contribution to journalArticle

Abstract

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.
Original languageEnglish
Pages (from-to)232-6
Number of pages5
JournalHypertension
Volume49
Issue number1
Early online date27 Nov 2006
DOIs
Publication statusPublished - Jan 2007

Keywords

  • pulmonary circulation
  • serotonin
  • hypoxia
  • transgenic animals

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    Morecroft, I., Dempsie, Y., Bader, M., Walther, D. J., Kotnik, K., Loughlin, L., Nilsen, M., & MacLean, M. R. (2007). Effect of tryptophan hydroxylase 1 deficiency on the development of hypoxia-induced pulmonary hypertension. Hypertension, 49(1), 232-6. https://doi.org/10.1161/01.HYP.0000252210.58849.78