Effect of tryptophan hydroxylase 1 deficiency on the development of hypoxia-induced pulmonary hypertension.
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.
Morecroft
Ian
I
Division of Neuroscience and Biomedical Systems, Faculty of Biomedical and Life Sciences, Glasgow University, Glasgow, Scotland.
Dempsie
Yvonne
Y
Bader
Michael
M
Walther
Diego J
DJ
Kotnik
Katarina
K
Loughlin
Lynn
L
Nilsen
Margaret
M
MacLean
Margaret R
MR
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
D018490:Serotonin Agents; D012701:Serotonin; C487801:Tph1 protein, mouse; D014365:Tryptophan Hydroxylase