Dual Effect of Serotonin on Growth of Bovine Pulmonary Artery Smooth Muscle Cells in Culture

• Published in: Circulation research 1991-05, Vol.68 (5), p.1362-1368
• Main Authors: Lee, S L, Wang, W W, Moore, B J, Fanburg, B L
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cattle; Cell Division - drug effects; Cells, Cultured; Cyclic AMP - analysis; Fundamental and applied biological sciences. Psychology; Iproniazid - pharmacology; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Pulmonary Artery - cytology; Pulmonary Artery - drug effects; Receptors, Serotonin - drug effects; Receptors, Serotonin - metabolism; Serotonin - metabolism; Serotonin - pharmacology; Striated muscle. Tendons; Vertebrates: osteoarticular system, musculoskeletal system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.res.68.5.1362

We have previously reported that serotonin (5-hydroxytryptamine [5HT]) alters cultured bovine pulmonary artery smooth muscle cell (SMC) configuration through two different regulatory mechanisms. We now report that 5HT also regulates SMC growth through these same two mechanisms — a stimulatory event initiated intracellularly and inhibition of growth resulting from a cell surface action. 5HT (1 μM) plus 0.1 mM iproniazid (a 5HT metabolic inhibitor) produced a severalfold stimulation of DNA synthesis (as measured by [H]thymidine incorporation) of SMCs after a 17–24-hour incubation with only a slight elevation of cellular cAMP. This stimulatory effect responded synergistically with other growth factors including platelet-derived growth factor, fibroblast growth factor, and epidermal growth factor and was effectively reversed by 5HT uptake inhibition. It was not produced by 5-hydroxyindoleacetic acid, a metabolite of 5HT. In the presence of 1 μM 5HT plus 0.1 mM isobutylmethylxanthine (IBMX), cAMP was elevated eightfold, dendritic formation occurred, and [H]thymidine labeling of SMCs was inhibited. Inhibition of labeling by [H]thymidine was mimicked by other agents that elevated cellular cAMP (10 μM histamine, 1 μM isoproterenol plus 0.1 mM IBMX, and 10 μM forskolin) and by 1 mM dibutyryl cAMP. This inhibitory effect was not blocked by either inhibition of 5HT uptake or 5HT-receptor antagonists ketanserin (5HT2); methiothepin, spiperone, and mianserin (5HT1/5HT2); and 3-tropanyl-indole-3-carboxylate and 3-tropanyl-3,5-dichlorobenzoate (5HT3). However, similar to 5HT, the 5HT1A agonist, (±)-8-hydroxy-(±)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthalenehydrobromide, in association with IBMX, produced an elevation in cAMP and inhibition of labeling by [H]thymidine. 5HT, in the presence of either iproniazid or IBMX, did not alter [Ca]i, indicating that [Ca]i was not a signal for either of these actions. The studies show that 5HT affects SMC growth at two foci of action, one intracellularly by a currently unknown mechanism and another at the cell surface, perhaps via a novel receptor and dependent on transduction of the signal through elevation of cAMP.