title: Signaling Pathways Linked to Serotonin-Induced Superoxide Anion Production: A Physiological Role for Mitochondria in Pulmonary Arteries.
abstract: Serotonin (5-HT) is a potent vasoconstrictor agonist and contributes to several vascular diseases including systemic or pulmonary hypertension and atherosclerosis. Although superoxide anion ([Formula: see text]) is commonly associated to cellular damages due to [Formula: see text] overproduction, we previously demonstrated that, in physiological conditions, [Formula: see text] also participates to the 5-HT contraction in intrapulmonary arteries (IPA). Here, we focused on the signaling pathways leading to [Formula: see text] production in response to 5-HT in rat IPA. Using electron paramagnetic resonance on rat IPA, we showed that 5-HT (100 μM)-induced [Formula: see text] production was inhibited by ketanserin (1 μM-an inhibitor of the 5-HT2receptor), absence of extracellular calcium, two blockers of voltage-independent calcium permeable channels (RHC80267 50 μM and LOE-908 10 μM) and a blocker of the mitochondrial complex I (rotenone-100 nM). Depletion of calcium from the sarcoplasmic reticulum or nicardipine (1 μM-an inhibitor of the L-type voltage-dependent calcium channel) had no effect on the 5-HT-induced [Formula: see text] production. [Formula: see text] levels were also increased by α-methyl-5-HT (10 μM-a 5-HT2receptors agonist) whereas GR127935 (1 μM-an antagonist of the 5-HT1B/Dreceptor) and citalopram (1 μM-a 5-HT transporter inhibitor) had no effect on the 5-HT-induced [Formula: see text] production. Peroxynitrites were increased in response to 5-HT (100 μM). In isolated pulmonary arterial smooth muscle cells loaded with rhod-2 or mitosox probes, we respectively showed that 5-HT increased both mitochondrial calcium and [Formula: see text] levels, which were both abrogated in absence of extracellular calcium. Mitochondrial [Formula: see text] levels were also abolished in the presence of rotenone (100 nM). In pulmonary arterial smooth muscle cells loaded with TMRM, we showed that 5-HT transiently depolarized the mitochondrial membrane whereas in the absence of extracellular calcium the mitochondrial membrane depolarisation was delayed and sustained in response to 5-HT. 5-HT decreased the mitochondrial respiratory rate measured with a Clark oxygen electrode. Altogether, in physiological conditions, 5-HT acts on 5-HT2receptors and induces an [Formula: see text] production dependent on extracellular calcium and mitochondria.
authors.affiliation: Centre de Recherche Cardio-Thoracique de Bordeaux, Institut National de la Santé et de la Recherche Médicale (INSERM), U1045Bordeaux, France; Centre de Recherche Cardio-Thoracique de Bordeaux, Université de BordeauxBordeaux, France.
authors.forename: Nafiisha
authors.initials: N
authors.lastname: Genet
authors.affiliation: Robert M. Berne Cardiovascular Research Center Charlottesville, VA, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Billaud
authors.affiliation: Maladies Rares: Génétique et Métabolisme, Université de Bordeaux Bordeaux, France.
authors.forename: Rodrigue
authors.initials: R
authors.lastname: Rossignol
authors.affiliation: Centre de Recherche Cardio-Thoracique de Bordeaux, Institut National de la Santé et de la Recherche Médicale (INSERM), U1045Bordeaux, France; Centre de Recherche Cardio-Thoracique de Bordeaux, Université de BordeauxBordeaux, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Dubois
authors.affiliation: Centre de Recherche Cardio-Thoracique de Bordeaux, Institut National de la Santé et de la Recherche Médicale (INSERM), U1045Bordeaux, France; Centre de Recherche Cardio-Thoracique de Bordeaux, Université de BordeauxBordeaux, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gillibert-Duplantier
authors.affiliation: Robert M. Berne Cardiovascular Research Center Charlottesville, VA, USA.
authors.forename: Brant E
authors.initials: BE
authors.lastname: Isakson
authors.affiliation: Centre de Recherche Cardio-Thoracique de Bordeaux, Institut National de la Santé et de la Recherche Médicale (INSERM), U1045Bordeaux, France; Centre de Recherche Cardio-Thoracique de Bordeaux, Université de BordeauxBordeaux, France.
authors.forename: Roger
authors.initials: R
authors.lastname: Marthan
authors.affiliation: Centre de Recherche Cardio-Thoracique de Bordeaux, Institut National de la Santé et de la Recherche Médicale (INSERM), U1045Bordeaux, France; Centre de Recherche Cardio-Thoracique de Bordeaux, Université de BordeauxBordeaux, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Savineau
authors.affiliation: Centre de Recherche Cardio-Thoracique de Bordeaux, Institut National de la Santé et de la Recherche Médicale (INSERM), U1045Bordeaux, France; Centre de Recherche Cardio-Thoracique de Bordeaux, Université de BordeauxBordeaux, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Guibert
keywords: 5-HT; calcium; mitochondria; pulmonary artery; superoxide anion