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Serotonin drives the activation of pulmonary artery adventitial fibroblasts and TGF-β1/Smad3-mediated fibrotic responses through 5-HT2A receptors

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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.

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Acknowledgments

This study was supported by the National Natural Science Foundation of China (Grant No. 81170294) and the State Key Program of the National Natural Science Foundation of China (Grant No. 30830051).

Conflict of interest

None declared.

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Authors and Affiliations

  1. 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

    Chunyan Chen, Fenling Fan, Ya Liu, Tingzhong Wang, Juanjuan Wang, Peijing Hu, Aiqun Ma & Hongyan Tian

  2. Department of Cardiology, Shaanxi Provincial People’s Hospital, Xi’an, 710068, Shaanxi, China

    Xinyuan Han

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  1. Chunyan Chen
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Correspondence to Aiqun Ma or Hongyan Tian.

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Chen, C., Han, X., Fan, F. et al. Serotonin drives the activation of pulmonary artery adventitial fibroblasts and TGF-β1/Smad3-mediated fibrotic responses through 5-HT2A receptors. Mol Cell Biochem 397, 267–276 (2014). https://doi.org/10.1007/s11010-014-2194-0

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