title: Serotonin drives the activation of pulmonary artery adventitial fibroblasts and TGF-β1/Smad3-mediated fibrotic responses through 5-HT(2A) receptors.
abstract: Pulmonary arterial remodeling is characterized by excessive proliferation, migration, and pro-differentiation and fibrotic activation of adventitial fibroblasts in pulmonary arterial hypertension (PAH) process. Several lines of evidence indicate that serotonin (5-HT) plays a central role in the pathogenesis of pulmonary arterial remodeling. In the present study, we investigated whether 5-HT is directly involved in the functional regulation of pulmonary artery adventitial fibroblasts (PAFs). Incubation of cultured rat PAFs with 5-HT caused a dose-dependent stimulation of cell proliferation, migration activity, and a time-dependent increase of α-SMA expression, a marker of fibroblast differentiation into myofibroblasts, and adventitia fibrosis, evaluating connective tissue growth factor (CTGF) and extracellular matrix (ECM) mRNAs and proteins. These effects were attenuated by the 5-HT2A receptor antagonist, ketanserin and mimicked by the 5-HT2A receptor agonist DOI. 5-HT-induced fibroblasts phenotypic alterations and ECM accumulation were dependent on stimulation of transforming growth factor (TGF)-β1 as demonstrated using a neutralizing antibody. 5-HT also caused Smad3 phosphorylation and ketanserin diminished 5-HT-induced Smad3 activation. These results demonstrated that 5-HT can directly activate PAFs through 5-HT2A receptor and promote fibroblasts phenotypic alterations and adventitia fibrosis depending on the signaling of the TGF-β1/Smad3 pathway.
authors.affiliation: Department of Cardiovascular Medicine, First Affiliated Hospital of the Medical College, Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061, Shaanxi, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Chen
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Han
authors.forename: Fenling
authors.initials: F
authors.lastname: Fan
authors.forename: Ya
authors.initials: Y
authors.lastname: Liu
authors.forename: Tingzhong
authors.initials: T
authors.lastname: Wang
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Wang
authors.forename: Peijing
authors.initials: P
authors.lastname: Hu
authors.forename: Aiqun
authors.initials: A
authors.lastname: Ma
authors.forename: Hongyan
authors.initials: H
authors.lastname: Tian
mesh_terms: D063194:Adventitia / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: C526316:CCN2 protein, rat; D044402:Receptor, Serotonin, 5-HT2A; D012702:Serotonin Antagonists; D051900:Smad3 Protein; C497787:Smad3 protein, rat; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D012701:Serotonin; D007650:Ketanserin