Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure and carries a very poor prognosis. Understanding of PAH pathogenesis is needed to support the development of new therapeutic strategies. Transforming growth factor β (TGF-β) drives vascular remodeling and increases vascular resistance by regulating differentiation and proliferation of smooth muscle cells (SMCs). Also, sphingosine-1-phosphate (S1P) has been implicated in PAH, but the relation between these two signaling mechanisms is not well understood. Here, we characterize the signaling networks downstream of TGF-β in human pulmonary arterial smooth muscle cells (HPASMCs), which involves mothers against decapentaplegic homolog (SMAD) signaling as well as Rho GTPases. Activation of Rho GTPases regulates myocardin-related transcription factor (MRTF) and serum response factor (SRF) transcription activity and results in upregulation of contractile gene expression. Our genetic and pharmacologic data show that in HPASMCs upregulation of α smooth muscle actin (αSMA) and calponin by TGF-β is dependent on both SMAD and Rho/MRTF-A/SRF transcriptional mechanisms.

中文翻译：

---

转化生长因子β1 通过增强 1-磷酸鞘氨醇信号传导增加人肺动脉平滑肌细胞收缩基因的表达

肺动脉高压（PAH）的特点是肺动脉压升高，预后很差。需要了解 PAH 的发病机制以支持新治疗策略的开发。转化生长因子β (TGF- β ) 通过调节平滑肌细胞 (SMC) 的分化和增殖来驱动血管重塑并增加血管阻力。此外，1-磷酸鞘氨醇 (S1P) 与多环芳烃有关，但这两种信号机制之间的关系尚不清楚。在这里，我们描述了 TGF- β下游的信号网络在人肺动脉平滑肌细胞 (HPASMCs) 中，这涉及母亲对抗十五项麻痹同系物 (SMAD) 信号以及 Rho GTP 酶。Rho GTPases 的激活调节心肌相关转录因子 (MRTF) 和血清反应因子 (SRF) 转录活性，并导致收缩基因表达的上调。我们的遗传和药理学数据表明，在 HPASMC 中，TGF- β对α平滑肌肌动蛋白 ( α SMA) 和钙调蛋白的上调依赖于 SMAD 和 Rho/MRTF-A/SRF 转录机制。