Poyatos Paula, Peinado Víctor I, Blanco Isabel, Osorio Jeisson, Yuan Shuai, Ramírez Ana M, Castellà Manuel, Rigol Montserrat, Solanes Núria, Straub Adam C, Barberà Joan Albert, Tura-Ceide Olga
Translational Research Group on Cardiovascular Respiratory Diseases (CAREs), Dr. Josep Trueta University Hospital de Girona, Santa Caterina Hospital de Salt and Institut d'Investigació Biomèdica de Girona (IDIBGI-CERCA), Parc Hospitalari Martí i Julià, Edifici M2, Salt 17190, Spain; Department of Medical Sciences, Faculty of Medicine, University of Girona, Girona, Spain.
Department of Pulmonary Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); University of Barcelona, Barcelona 08036, Spain; Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), Madrid, Spain; Department of Experimental Pathology, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), CSIC-IDIBAPS, Barcelona, Spain.
Biomed Pharmacother. 2025 Sep;190:118425. doi: 10.1016/j.biopha.2025.118425. Epub 2025 Aug 4.
Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by the presence of organized clots obstructing the pulmonary arteries. Pulmonary endarterectomy (PEA) is the standard treatment, but in cases of inoperability, Riociguat, a soluble guanylate cyclase (sGC) stimulator, is the only approved pharmacological option. Endothelial dysfunction (ED) plays a central role, with the NO/sGC/cGMP pathway being critically involved. The aim of this study is to identify the molecular pathways contributing to ED and assess the therapeutic potential of Riociguat, BAY 60-2770, and Sildenafil in reinstating vascular homeostasis.
Endothelial cells (ECs) were isolated from PEA specimens of individuals diagnosed with CTEPH (CTEPH-EC). ECs derived from healthy pulmonary arteries (HPAECs) were used as controls. Cells were treated with different concentrations of Riociguat, BAY-60-2770 and Sildenafil, followed by functional assays, transcriptomic, and molecular analyses.
The drugs used induced significant effects on endothelial cell dynamics, including decreased proliferation, increased apoptosis, and enhanced angiogenesis both in vitro and in vivo. Transcriptomic analysis followed by validation studies identified significant alterations in genes related to angiogenesis, with marked changes observed following BAY 60-2770 treatment. Dysregulation in the ERK/eNOS/PKG signaling pathway was demonstrated in CTEPH-EC compared to HPAEC at both the gene and protein level. Treatment with Riociguat and Sildenafil restored ERK/eNOS, but not PKG signaling.
Therapeutic approaches targeting endothelial dysfunction and the NO/sGC pathway in CTEPH partially restore endothelial function, highlighting the dual action of Riociguat and Sildenafil, stimulating sGC while exerting upstream effects by enhancing eNOS signaling. These findings underscore the importance of targeted pharmacological approaches to improve patient outcomes.
慢性血栓栓塞性肺动脉高压（CTEPH）的特征是存在阻塞肺动脉的机化血栓。肺动脉内膜剥脱术（PEA）是标准治疗方法，但对于无法手术的病例，利奥西呱（一种可溶性鸟苷酸环化酶（sGC）刺激剂）是唯一获批的药物选择。内皮功能障碍（ED）起着核心作用，NO/sGC/cGMP途径至关重要。本研究的目的是确定导致ED的分子途径，并评估利奥西呱、BAY 60-2770和西地那非在恢复血管稳态方面的治疗潜力。
从诊断为CTEPH的个体的PEA标本中分离内皮细胞（CTEPH-EC）。来自健康肺动脉的内皮细胞（HPAECs）用作对照。细胞用不同浓度的利奥西呱、BAY-60-2770和西地那非处理，然后进行功能测定、转录组学和分子分析。
所用药物对内皮细胞动力学产生显著影响，包括体外和体内细胞增殖减少、凋亡增加和血管生成增强。转录组分析及后续验证研究确定了与血管生成相关基因的显著改变，BAY 60-2770处理后观察到明显变化。与HPAEC相比,CTEPH-EC在基因和蛋白质水平均显示ERK/eNOS/PKG信号通路失调。利奥西呱和西地那非治疗可恢复ERK/eNOS，但不能恢复PKG信号。
针对CTEPH内皮功能障碍和NO/sGC途径的治疗方法可部分恢复内皮功能，突出了利奥西呱和西地那非的双重作用，即刺激sGC同时通过增强eNOS信号发挥上游作用。这些发现强调了靶向药物治疗方法对改善患者预后的重要性。
