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CARDIOVASCULAR

Evidence for a Control of Plasma Serotonin Levels by 5-Hydroxytryptamine_2B Receptors in Mice

Services de Biochimie et d'Hématologie Biologique, Hôpital Lariboisière, Assistance Publique-Hopitaux de Paris, Paris, France (J.C., K.P., C.T., L.D., J.M.L.); Institut Federatif de Recherche 139, Paris, France (J.C., K.P., C.T., L.D., J.M.L.); Institut de Génétique et Biologie Moléculaire et Cellulaire, Illkirch, France (J.M.E., L.M.); Institut National de la Santé et de la Recherche Médicale U536, Illkirch, France (J.M.E., L.M.); Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7104, Illkirch, France (J.M.E., L.M.); University of Strasbourg, Illkirch, France (J.M.E., L.M.); Laboratoire de Chirurgie Expérimentale Unité Propre de Recherche et de l'Enseignement Supérieur, Equipe d'Accueil, Paris South University, Hôpital Marie Lannelongue, Le Plessis-Robinson, France (P.H.); Institut National de la Santé et de la Recherche Médicale U616, Paris, France (L.M.); Hopital Pitié-Salpetrière, Paris, France (L.M.); and University Pierre et Marie Curie, Paris, France (L.M.)

A correlation between high plasma serotonin levels and total pulmonary resistance was reported in more than 80% of pulmonary hypertensive patients. When submitted to chronic hypoxia (10% O₂ for more than 3 weeks), wild-type mice develop lung vascular remodeling and pulmonary hypertension. We previously reported that, in contrast, the development of these hypoxia-dependent alterations is totally abolished in mice with permanent (genetic) or transient (pharmacologic) inactivation of the serotonin 5-hydroxytryptamine (5-HT)_2B receptor. In the present study, we asked whether 5-HT_2B receptors could be involved in the control of plasma serotonin levels. Further investigating the chronic hypoxic mouse model of pulmonary hypertension, we first show that in wild-type mice, plasma serotonin levels and 5-HT_2B receptors expression were significantly increased after chronic exposure to hypoxia. This increase appeared before significant changes in remodeling factors could be detected and persisted when the pathology was established. Conversely, in mice with either genetically or pharmacologically inactive 5-HT_2B receptors, plasma serotonin levels were not modified by chronic hypoxia. We then confirmed that 5-HT_2B receptors can control plasma serotonin levels by providing in vivo evidence that an acute agonist stimulation of 5-HT_2B receptor triggers a transient increase in plasma serotonin that is serotonin transporter dependent and blocked by 5-HT_2B receptor-selective antagonist or genetic ablation. Our data support the notion that a 5-HT_2B receptor-dependent regulation of serotonin uptake is implicated in the control of plasma serotonin levels.

Address correspondence to: Dr. Luc Maroteaux, Institut National de la Santé et de la Recherche Médicale, U616, Hopital Pitié-Salpetrière, Université Pierre et Marie Curie Paris, Bat Pédiatrie, 47 Boulevard de l'Hopital, 75013 Paris, France. E-mail: luc.maroteaux{at}chups.jussieu.fr

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