Published online before print April 13, 2006, doi: 10.1161/01.RES.0000222546.45372.a0
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Submitted on October 29, 2005
Revised on March 16, 2006
Accepted on April 5, 2006
Transgenic Mice Overexpressing the 5-Hydroxytryptamine Transporter Gene in Smooth Muscle Develop Pulmonary Hypertension
Christophe Guignabert ;
From the INSERM U651 and Département de Physiologie (C.G., M.I., L.I.T., P.Z., A.-M.B.-M., S.A., S.E.), Hôpital H. Mondor, AP-HP, Créteil; UMR 677 INSERM/UPMC (N.H., M.H.), NeuroPsychoPharmacologie, Faculté de Médecine Pitié- Salpêtrière, Paris; Laboratoire de Biologie Moléculaire de la Différentiation (Z.L.), Paris VII University, France; and Center for Genetic Lung Disease (D.R.), University of Colorado at Denver Health Sciences Center.
* To whom correspondence should be addressed. E-mail: saadia.eddahibi{at}creteil.inserm.fr.
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.
Key words: serotonin transporter • pulmonary hypertension • vascular smooth muscle • transgenic mice
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