Abstract
5-Hydroxytryptamine (5-HT) plays an important role in the remodeling of the pulmonary circulation, notably during exposure to hypoxia. Here, we have been interested in the role of 5-HT and the 5-HT transporter in the proliferation of pulmonary artery fibroblasts derived from pulmonary hypertensive animals and particularly in defining which receptor subtype is of importance and in identifying a possible mechanism of this effect. This study has examined the effects of 5-HT on the proliferation and activation of mitogen-activated protein kinases in rat pulmonary artery fibroblasts from control and chronically hypoxic animals. We have shown that 5-HT has a co-mitogenic effect with serum to produce an enhanced proliferative response in cells from chronically hypoxic rats over those from control animals. Moreover we have found that the 5-HT(2A) receptor is responsible for the hypoxia-associated 5-HT proliferation in these cells by using specific receptor agonist and antagonist studies and that this receptor signals via p38 mitogen-activated protein kinase. We have also shown that the 5-HT transporter is important in the mitogenic response not pertaining to hypoxic stimulation. Taken together, these data suggest that selective 5-HT(2A) receptor antagonists may have a role in pulmonary artery fibroblast proliferation to hypoxia.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carrier Proteins / metabolism*
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Cell Division / drug effects
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Cell Division / physiology
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Cells, Cultured
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Disease Models, Animal
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Fibroblasts / drug effects
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Fibroblasts / metabolism*
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Fibroblasts / pathology*
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Hypertension, Pulmonary / complications
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Hypertension, Pulmonary / metabolism*
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Hypertension, Pulmonary / pathology*
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Hypoxia / enzymology
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Hypoxia / etiology
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Hypoxia / pathology
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Membrane Glycoproteins / metabolism*
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Membrane Transport Proteins*
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Mitogen-Activated Protein Kinases / drug effects
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Mitogen-Activated Protein Kinases / metabolism*
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Nerve Tissue Proteins / metabolism*
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Phosphorylation / drug effects
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Pulmonary Artery / pathology
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Rats
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Receptor, Serotonin, 5-HT2A / metabolism
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Serotonin / metabolism*
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Serotonin / pharmacology
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Serotonin Antagonists / pharmacology
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Serotonin Plasma Membrane Transport Proteins
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Serotonin Receptor Agonists / pharmacology
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Signal Transduction / drug effects
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Signal Transduction / physiology
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p38 Mitogen-Activated Protein Kinases
Substances
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Carrier Proteins
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Membrane Glycoproteins
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Membrane Transport Proteins
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Nerve Tissue Proteins
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Receptor, Serotonin, 5-HT2A
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Serotonin Antagonists
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Serotonin Plasma Membrane Transport Proteins
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Serotonin Receptor Agonists
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Slc6a4 protein, rat
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Serotonin
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases