Effect of tryptophan hydroxylase 1 deficiency on the development of hypoxia-induced pulmonary hypertension

Hypertension. 2007 Jan;49(1):232-6. doi: 10.1161/01.HYP.0000252210.58849.78. Epub 2006 Nov 27.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Hypertension, Pulmonary / etiology*
  • Hypertension, Pulmonary / physiopathology
  • Hypertrophy, Right Ventricular / etiology
  • Hypoxia / complications*
  • Hypoxia / physiopathology
  • Mice
  • Mice, Knockout
  • Pressure
  • Pulmonary Artery / drug effects
  • Pulmonary Artery / physiopathology
  • Serotonin / pharmacology
  • Serotonin Agents / pharmacology
  • Tryptophan Hydroxylase / deficiency*
  • Vascular Resistance
  • Vasoconstriction
  • Ventricular Function, Right


  • Serotonin Agents
  • Serotonin
  • Tph1 protein, mouse
  • Tryptophan Hydroxylase