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Published as doi: 10.1096/fj.06-8058com.
 (The FASEB Journal. 2007;21:2725-2734.)
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The 5-HT transporter transactivates the PDGFß receptor in pulmonary artery smooth muscle cells

Yinglin Liu, Min Li, Rod R. Warburton, Nicholas S. Hill and Barry L. Fanburg1

Tufts-New England Medical Center, Pulmonary, Critical Care and Sleep Division, Tupper Research Institute, Boston, Massachusetts, USA

1Correspondence: Pulmonary, Critical Care and Sleep Division, Tufts-New England Medical Center, 750 Washington St., #257, Boston, MA 02111, USA. E-mail: bfanburg{at}tufts-nemc.org

Serotonin (5-HT) stimulates smooth muscle cell growth through 5-HT receptors and the 5-HT transporter (5-HTT), and has been associated with pulmonary hypertension (PH). Platelet-derived growth factor receptors (PDGFR) have also been associated with PH. We present evidence for the first time that 5-HT transactivates PDGFRß through the 5-HTT in pulmonary artery (PA) SMCs. Inhibition of PDGFR kinase with imatinib or AG1296 blocks 5-HT-stimulated PDGFRß phosphorylation. 5-HTT inhibitors and the Na+/K+-ATPase inhibitor ouabain, but not 5-HT2 and 5-HT1B/1D receptor inhibitors, block PDGFRß activation by 5-HT. Notably, 5-HTT binds the PDGFRß upon 5-HT stimulation and the 5-HTT inhibitor fluoxetine blocks both the binding and PDGDRß activation. Activation of PDGFRß may occur through oxidation of a catalytic cysteine of tyrosine phosphatase. 5-HT-activated PDGFRß phosphorylation is blocked by the antioxidant N-acetyl-L-cysteine and the NADPH oxidase inhibitor, DPI. Inhibition of PDGFR kinase with imatinib or AG1296 significantly inhibits SMC proliferation and migration induced by 5-HT in vitro. Infusion of 5-HT by miniosmotic pumps enhances PDGFRß activation in mouse lung in vivo. In summary, these results demonstrate that 5-HT transactivates PDGFRß in PASMCs leading to SMC proliferation and migration, and may be an important signaling pathway in the production of PH in vivo.—Liu, Y., Li, M., Warburton, R. R., Hill, N. S., Fanburg, B. L. The 5-HT transporter transactivates the PDGFß receptor in pulmonary artery smooth muscle cells.


Key Words: serotonin • pulmonary hypertension




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