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Proliferation and Signaling in Fibroblasts

Role of 5-Hydroxytryptamine_2A Receptor and Transporter

Scottish Pulmonary Vascular Unit and Department of Immunology, Western Infirmary; and Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom

Correspondence and requests for reprints should be addressed to David J. Welsh, B.Sc., Ph.D., Scottish Pulmonary Vascular Unit, Level 8, Western Infirmary, Glasgow G11 6NT, UK. E-mail: david.welsh{at}bio.gla.ac.uk

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.

Key Words: fibroblasts • hypoxia • pulmonary • pulmonary hypertension • 5-hydroxytryptamine

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