Serotonin drives the activation of pulmonary artery adventitial fibroblasts and TGF-β1/Smad3-mediated fibrotic responses through 5-HT2A receptors
Serotonin drives the activation of pulmonary artery adventitial fibroblasts and TGF-β1/Smad3-mediated fibrotic responses through 5-HT2A receptors
复制标题
DOI：
10.1007/s11010-014-2194-0
复制
发表时间：
2014-12-01
影响因子：
4.3
通讯作者：
Tian, Hongyan
中科院分区：
文献类型：
--
作者：
Chen, Chunyan;Han, Xinyuan;Tian, Hongyan
肺动脉重构是肺动脉高压（PAH）过程中血管外膜成纤维细胞过度增殖、迁移、促分化和纤维化活化的特征。多种证据表明，5-羟色胺（5-HT）在肺动脉重构的发病机制中起着重要作用。在本研究中，我们研究了5-HT是否直接参与肺动脉外膜成纤维细胞（PAF）的功能调节。培养的大鼠PAF与5-HT孵育引起细胞增殖的剂量依赖性刺激，迁移活性，和α-SMA表达的时间依赖性增加，成纤维细胞分化为肌成纤维细胞和外膜纤维化的标志物，评价结缔组织生长因子（CTGF）和细胞外基质（ECM）mRNA和蛋白质。这些作用被5-HT 2A受体拮抗剂酮色林减弱，并被5-HT 2A受体激动剂DOI模拟。5-HT诱导的成纤维细胞表型改变和ECM积累依赖于转化生长因子（TGF）-β 1的刺激，如使用中和抗体所示。5-HT还引起Smad 3磷酸化，酮色林减弱5-HT诱导的Smad 3活化。这些结果表明，5-HT可通过5-HT 2A受体直接激活PAF，并通过TGF-β 1/Smad 3信号通路促进成纤维细胞表型改变和外膜纤维化。
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 alpha-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)-beta 1 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-beta 1/Smad3 pathway.