Transgenic mice overexpressing the 5-hydroxytryptamine transporter gene in smooth muscle develop pulmonary hypertension

Circ Res. 2006 May 26;98(10):1323-30. doi: 10.1161/01.RES.0000222546.45372.a0. Epub 2006 Apr 13.


One intrinsic abnormality of pulmonary artery smooth muscle cells (PA-SMCs) in human idiopathic pulmonary hypertension (iPH) is an exaggerated proliferative response to internalized serotonin (5-HT) caused by increased expression of the 5-HT transporter (5-HTT). To investigate whether 5-HTT overexpression in PA-SMCs is sufficient to produce PH, we generated transgenic mice overexpressing 5-HTT under the control of the SM22 promoter. Studies in SM22-LacZ(+) mice showed that the transgene was expressed predominantly in SMCs of pulmonary and systemic vessels. Compared with wild-type mice, SM22-5-HTT(+) mice exhibited a 3- to 4-fold increase in lung 5-HTT mRNA and protein, together with increased lung 5-HT uptake activity, but no changes in platelet 5-HTT activity or blood 5-HT levels. At 8 weeks of age, SM22-5-HTT(+) mice exhibited PH, with marked increases in right ventricular systolic pressure (RVSP), right ventricle/left ventricle+septum ratio, and muscularization of distal pulmonary vessels, but no changes in systemic arterial pressure. PH worsened with age. Except a marked decrease in Kv channels, no changes in the lung expression of mediators of pulmonary vascular remodeling were observed in SM22-5-HTT(+) mice. Compared with wild-type mice, SM22-5-HTT(+) mice showed depressed hypoxic pulmonary vasoconstriction contrasting with greater severity of hypoxia- or monocrotaline-induced PH. These results show that increased 5-HTT expression in PA-SMCs, to a level close to that found in human iPH, lead to PH in mice. They further support a central role for 5-HTT in the pathogenesis of PH, making 5-HTT a potential therapeutic target.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Blood Pressure
  • Blood Vessels / physiopathology
  • Humans
  • Hydroxyindoleacetic Acid / blood
  • Hypertension, Pulmonary / chemically induced
  • Hypertension, Pulmonary / etiology*
  • Hypertension, Pulmonary / metabolism
  • Hypertension, Pulmonary / physiopathology
  • Hypoxia / physiopathology
  • Lung / metabolism
  • Mice
  • Mice, Transgenic
  • Monocrotaline / analogs & derivatives
  • Muscle, Smooth, Vascular / metabolism*
  • Pulmonary Artery
  • Serotonin Plasma Membrane Transport Proteins / blood
  • Serotonin Plasma Membrane Transport Proteins / genetics
  • Serotonin Plasma Membrane Transport Proteins / metabolism*
  • Tissue Distribution
  • Transgenes / physiology
  • Vasoconstriction
  • Ventricular Function, Right


  • Serotonin Plasma Membrane Transport Proteins
  • monocrotaline pyrrole
  • Hydroxyindoleacetic Acid
  • Monocrotaline