%0 Journal Article %T Transgenic mice overexpressing the 5-hydroxytryptamine transporter gene in smooth muscle develop pulmonary hypertension. %T Pulmonary Hypertension in Transgenic 5-HTT+ Mice %+ Fonctions Cellulaires et Moleculaires de l'Appareil Respiratoire et des Vaisseaux %+ Laboratoire de biologie moléculaire de la différenciation %+ CHU Pitié-Salpêtrière [AP-HP] %+ Center for Genetic Lung Disease %A Guignabert, Christophe %A Izikki, Mohamed %A Tu, Ly Ieng %A Li, Zhenlin %A Zadigue, Patricia %A Barlier-Mur, Anne-Marie %A Hanoun, Naïma %A Rodman, David %A Hamon, Michel %A Adnot, Serge %A Eddahibi, Saadia %Z This research was supported by grants from INSERM, the Ministe're de la Recherche, the De'le'gation a' la Recherche Clinique de l'AP-HP, and the Fondation de France. The study was performed with the support of the "plate-forme petit animal" IFR10, Creteil, France. %Z 9 pages %< avec comité de lecture %@ 0009-7330 %J Circulation Research %I American Heart Association %V 98 %N 10 %P 1323-30 %8 2006-05-26 %D 2006 %R 10.1161/01.RES.0000222546.45372.a0 %M 16614302 %K serotonin transporter %K pulmonary hypertension %K vascular smooth muscle %K transgenic mice %Z Life Sciences [q-bio]/Cellular Biology %Z Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract %Z Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system %Z Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] %Z Life Sciences [q-bio]/Genetics %Z Life Sciences [q-bio]/Human health and pathologyJournal articles %X 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. %G English %2 https://inserm.hal.science/inserm-00499636/document %2 https://inserm.hal.science/inserm-00499636/file/Guignabert_et_al_Circ_Res.pdf %L inserm-00499636 %U https://inserm.hal.science/inserm-00499636 %~ INSERM %~ UNIV-PARIS7 %~ APHP %~ CARDIO %~ UPEC %~ SORBONNE-UNIVERSITE %~ SU-INF-2018 %~ SU-MEDECINE %~ SU-MED %~ UNIV-PARIS %~ SU-TI %~ ALLIANCE-SU