Nafiisha Genet, Marie Billaud, Rodrigue Rossignol, Mathilde Dubois, Jennifer Gillibert-Duplantier, Brant E. Isakson, Roger Marthan, Jean-Pierre Savineau, Christelle Guibert
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-HT2 receptor), 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-HT2 receptors agonist) whereas GR127935 (1 μM-an antagonist of the 5-HT1B/D receptor) 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-HT2 receptors and induces an [Formula: see text] production dependent on extracellular calcium and mitochondria.
Pharmacology, Toxicology and Pharmaceutical Science
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4%
Unspecified
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4%
Other
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4%
Unknown
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27%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 13 February 2017.
All research outputs
#20,306,103
of 25,820,938 outputs
Outputs from Frontiers in Physiology
#8,160
of 15,733 outputs
Outputs of similar age
#309,230
of 427,158 outputs
Outputs of similar age from Frontiers in Physiology
#143
of 232 outputs
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So far Altmetric has tracked 15,733 research outputs from this source. They typically receive more attention than average, with a mean Attention Score of 8.2. This one is in the 41st percentile – i.e., 41% of its peers scored the same or lower than it.
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