IntroductionWe recently reported that overexpression of the 5-hydroxytryptamine transporter (5-HTT) and its subséquent effects on pulmonary artery smooth muscle (PA-SMC) prolifération represents a genetic prédisposition to develop pulmonary hypertension (PH) in humans. In this study, we questioned whether 5-HTT overexpression alone is sufficient to produce the PH pheno-type in the absence of other stimuli or given a proper environmental stimulus.MethodsTo this end, we generated transgenic mice overexpressing 5-HTT selectively in SMC by using the SM22 promoter.ResultsAs compared to wild-type mice (WT), transgenic SM22p-5-HTT+ mice exhibited a 4- to 5-fold increase in lung 5-HTT mRNA and protein (QRT-PCR and citalopram binding) which was predominantly located in vascular SMC (5-HTT immu-nostaining). SM22p-5-HTT+ mice studied at 8 weeks of âge deve-loped PH as reflected by significant increases in (i) right ventricular systolic pressure (RVSP): 231 mmHgvs162 mmHg in WT (p < 0.01), (ii) Fulton index (RV/LV+S ratio): 343% vs 262% in WT (p < 0.01), and (iii) muscularization of distal pulmonary vessels (p < 0.01). Pulmonary hypertension worsened while SM22p-5-HTT+ mice became older, RVSP reaching 303 mmHg at 20 weeks of âge. Transgenic SM22p-5-HTT+ mice also showed an exacerbated pulmonary hypertensive response to 2 wk exposure to hypoxia (RVSP: 433 mmHgvs312 mmHg p < 0.01) or to 5 mg/kg monocrotaline pyrole administration (RVSP: 383 mmHgvs272 mmHg p < 0.01) in SM22p-5-HTT+vsWT respectively.ConclusionsThèse results indicating that 5-HTT overexpression in PA-SMCs is sufficient alone to cause PH are in accordance with the proposai that 5-HTT overexpression plays a primary rôle in the pathogenesis of human PH.