The 5-HT transporter transactivates the PDGFbeta receptor in pulmonary artery smooth muscle cells.
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 PDGFRbeta through the 5-HTT in pulmonary artery (PA) SMCs. Inhibition of PDGFR kinase with imatinib or AG1296 blocks 5-HT-stimulated PDGFRbeta phosphorylation. 5-HTT inhibitors and the Na+/K+-ATPase inhibitor ouabain, but not 5-HT2 and 5-HT1B/1D receptor inhibitors, block PDGFRbeta activation by 5-HT. Notably, 5-HTT binds the PDGFRbeta upon 5-HT stimulation and the 5-HTT inhibitor fluoxetine blocks both the binding and PDGDRbeta activation. Activation of PDGFRbeta may occur through oxidation of a catalytic cysteine of tyrosine phosphatase. 5-HT-activated PDGFRbeta 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 PDGFRbeta activation in mouse lung in vivo. In summary, these results demonstrate that 5-HT transactivates PDGFRbeta in PASMCs leading to SMC proliferation and migration, and may be an important signaling pathway in the production of PH in vivo.
Liu
Yinglin
Y
Pulmonary, Critical Care and Sleep Division, Tufts-New England Medical Center, 750 Washington St., Boston, MA 02111, USA.
Li
Min
M
Warburton
Rod R
RR
Hill
Nicholas S
NS
Fanburg
Barry L
BL
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D047468:Immunoprecipitation; D008168:Lung / Q000378:metabolism; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000008:administration & dosage / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction; D053778:Thiazolidines / Q000494:pharmacology; D015533:Transcriptional Activation; D014443:Tyrosine / Q000378:metabolism; D014945:Wound Healing
D000975:Antioxidants; D017382:Reactive Oxygen Species; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D053778:Thiazolidines; D012701:Serotonin; D014443:Tyrosine; D020797:Receptor, Platelet-Derived Growth Factor beta; D017027:Protein Tyrosine Phosphatases