Zou Xiaozhou, Yuan Mengnan, Zhou Wei, Cai Anqi, Cheng Yili, Zhan Zibo, Zhang Yiwen, Pan Zongfu, Hu Xiaoping, Zheng Shuilian, Liu Ting, Huang Ping
Center for Clinical Pharmacy, Cancer Center, and Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China.
Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Hangzhou, China.
Am J Respir Cell Mol Biol. 2025 Apr;72(4):364-379. doi: 10.1165/rcmb.2023-0355OC.
Endothelial-to-mesenchymal transition (EndMT) has been reported to contribute to pulmonary vascular remodeling in patients with pulmonary hypertension (PH). Our study demonstrates that SOX17, a member of the SOX (SRY-Box) transcription factor family, plays a role in regulating pulmonary arterial homeostasis through extracellular vesicles in an autocrine and paracrine manner. However, the role of SOX17 in mediating EndMT of pulmonary arterial endothelial cells (PAECs) and its intracellular mechanisms remain unclear. Here we present evidence showing that downregulation of SOX17 expression is accompanied by significant pulmonary arterial EndMT and activation of the TGF-β/Smad2/3 signaling pathway in patients with idiopathic PH and rats with PH induced by Sugen 5416/hypoxia. In primary human PAECs, canonical TGF-β (transforming growth factor-β) signaling inhibits the expression of SOX17. Overexpression of SOX17 reverses TGF-β- and hypoxia-induced EndMT. These findings suggest that SOX17 is essential for human PAECs to undergo TGF-β-mediated EndMT. Mechanistically, our data demonstrate that SOX17 prevents TGF-β-induced EndMT by suppressing ROCK1 (Rho-associated kinase 1) expression through binding to the specific promoter region of ROCK1, thereby inhibiting MYPT1 (myosin phosphatase target subunit 1) and MLC (myosin light chain) phosphorylation. Furthermore, we show that Tie2-Cre rats with endothelial cell-specific overexpression of SOX17 are protected against Sugen/hypoxia-induced EndMT and subsequent pulmonary vascular remodeling. Consistent with the results, compared with Tie2-Cre rats treated with Sugen/hypoxia alone, rats overexpressing SOX17 exhibited reduced levels of ROCK1 as well as decreased phosphorylation levels of MYPT1 and MLC. Overall, our studies unveil a novel TGF-β/SOX17/ROCK1 pathway involved in regulating PAECs' EndMT process, and we propose the targeting of SOX17 as a potential therapeutic strategy for alleviating pulmonary vascular remodeling in PH.
据报道，内皮向间充质转化（EndMT）参与了肺动脉高压（PH）患者的肺血管重塑。我们的研究表明，SOX（SRY盒）转录因子家族成员SOX17通过细胞外囊泡以自分泌和旁分泌方式在调节肺动脉稳态中发挥作用。然而，SOX17在介导肺动脉内皮细胞（PAECs）的EndMT中的作用及其细胞内机制仍不清楚。在此，我们提供证据表明，在特发性PH患者和用Sugen 5416/低氧诱导的PH大鼠中，SOX17表达下调伴随着显著的肺动脉EndMT和TGF-β/Smad2/3信号通路的激活。在原代人PAECs中，经典的TGF-β（转化生长因子-β）信号抑制SOX17的表达。SOX17的过表达逆转了TGF-β和低氧诱导的EndMT。这些发现表明，SOX17对于人PAECs经历TGF-β介导的EndMT至关重要。机制上，我们的数据表明，SOX17通过与ROCK1（Rho相关激酶1）的特定启动子区域结合来抑制ROCK1表达，从而防止TGF-β诱导的EndMT，进而抑制MYPT1（肌球蛋白磷酸酶靶向亚基1）和MLC（肌球蛋白轻链）的磷酸化。此外，我们表明，在内皮细胞特异性过表达SOX17的Tie2-Cre大鼠中，可免受Sugen/低氧诱导的EndMT和随后的肺血管重塑。与结果一致，与单独用Sugen/低氧处理的Tie2-Cre大鼠相比，过表达SOX17的大鼠ROCK1水平降低，MYPT1和MLC的磷酸化水平也降低。总体而言，我们的研究揭示了一条参与调节PAECs的EndMT过程的新型TGF-β/SOX17/ROCK1途径，并且我们提出靶向SOX17作为缓解PH中肺血管重塑的潜在治疗策略。
