Transgenic mice overexpressing the 5-hydroxytryptamine transporter gene in smooth muscle develop pulmonary hypertension.
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.
Guignabert
Christophe
C
INSERM U651, Département de Physiologie, Hôpital H. Mondor, AP-HP, Créteil, France.
Izikki
Mohamed
M
Tu
Ly Ieng
LI
Li
Zhenlin
Z
Zadigue
Patricia
P
Barlier-Mur
Anne-Marie
AM
Hanoun
Naïma
N
Rodman
David
D
Hamon
Michel
M
Adnot
Serge
S
Eddahibi
Saadia
S
D000208:Acute Disease; D000818:Animals; D001794:Blood Pressure; D001808:Blood Vessels / Q000503:physiopathology; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000097:blood; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000503:physiopathology; D008168:Lung / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D016686:Monocrotaline / Q000031:analogs & derivatives; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D011651:Pulmonary Artery; D050486:Serotonin Plasma Membrane Transport Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D014018:Tissue Distribution; D019076:Transgenes / Q000502:physiology; D014661:Vasoconstriction; D016278:Ventricular Function, Right
D050486:Serotonin Plasma Membrane Transport Proteins; C014114:monocrotaline pyrrole; D006897:Hydroxyindoleacetic Acid; D016686:Monocrotaline