title: Effect of tryptophan hydroxylase 1 deficiency on the development of hypoxia-induced pulmonary hypertension.
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.
authors.affiliation: Division of Neuroscience and Biomedical Systems, Faculty of Biomedical and Life Sciences, Glasgow University, Glasgow, Scotland.
authors.forename: Ian
authors.initials: I
authors.lastname: Morecroft
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Dempsie
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.forename: Diego J
authors.initials: DJ
authors.lastname: Walther
authors.forename: Katarina
authors.initials: K
authors.lastname: Kotnik
authors.forename: Lynn
authors.initials: L
authors.lastname: Loughlin
authors.forename: Margaret
authors.initials: M
authors.lastname: Nilsen
authors.forename: Margaret R
authors.initials: MR
authors.lastname: MacLean
mesh_terms: D000818:Animals; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000209:etiology; D000860:Hypoxia / Q000150:complications* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D011312:Pressure; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D012701:Serotonin / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology; D014365:Tryptophan Hydroxylase / Q000172:deficiency*; D014655:Vascular Resistance; D014661:Vasoconstriction; D016278:Ventricular Function, Right
chemical_list: D018490:Serotonin Agents; D012701:Serotonin; C487801:Tph1 protein, mouse; D014365:Tryptophan Hydroxylase