Knoepp Fenja, Abid Shariq, Houssaini Amal, Lipskaia Larissa, Gökyildirim Mira Yasemin, Born Emmanuelle, Marcos Elisabeth, Arhatte Malika, Glogowska Edyta, Vienney Nora, Günther Andreas, Kraut Simone, Breitenborn-Mueller Ingrid, Quanz Karin, Fenner-Nau Dagmar, Derumeaux Geneviève, Weissmann Norbert, Honoré Eric, Adnot Serge
Excellence Cluster Cardio-Pulmonary Institute, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Justus Liebig University (F.K., M.Y.G., A.G., S.K., I.B.-M., K.Q., D.F.-N., N.W.).
Département de Physiologie-Explorations Fonctionnelles and FHU SENEC Hôpital Henri Mondor, French National Institute of Health and Medical Research Unit 955, AP-HP, Créteil, France (S. Abid, A.H., L.L., E.B., E.M., N.V., G.D., S. Adnot).
Circ Res. 2025 Apr 25;136(9):1031-1048. doi: 10.1161/CIRCRESAHA.124.325475. Epub 2025 Apr 4.
Pulmonary hypertension (PH) is a life-threatening and progressive yet incurable disease. The hallmarks of PH comprise (1) sustained contraction and (2) excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs). A major stimulus to which PASMCs are exposed during PH development is altered mechanical stress, originating from increased blood pressure, changes in blood flow velocity, and a progressive stiffening of pulmonary arteries. Mechanosensitive ion channels, including Piezo1 (Piezo-type mechanosensitive ion channel component-1), perceive such mechanical stimuli and translate them into a variety of cellular responses, including contractility or proliferation. Thus, the objective of the present study was to elucidate the specific role of Piezo1 in PASMCs for PH development and progression.
The cell-type specific function of Piezo1 in PH was assessed in (1) PASMCs and lung tissues from patients with PH and (2) 2 mouse strains characterized by smooth muscle cell-specific, conditional Piezo1 knockout. Taking advantage of these strains, the smooth muscle cell-specific role of Piezo1 in PH development and progression was assessed in isolated, perfused, and ventilated mouse lungs, wire myography, and proliferation assays. Finally, in vivo function of smooth muscle cell-specific Piezo1 knockout was evaluated upon induction of chronic hypoxia-induced PH in these mice with insights into pulmonary vascular cell senescence.
Compared with healthy controls, PASMCs from patients with PH featured an elevated Piezo1 expression and increased proliferative phenotype. Smooth muscle cell-specific Piezo1 deletion, as confirmed via quantitative real-time polymerase chain reaction and patch clamp recordings, prevented the hypoxia-induced increase in PASMC proliferation in mice. Moreover, Piezo1 knockout reduced hypoxic pulmonary vasoconstriction in isolated, perfused, and ventilated mouse lungs, endothelial-denuded pulmonary arteries, and hemodynamic measurements in vivo. Consequently, -deficient mice were considerably protected against chronic hypoxia-induced PH development with ameliorated right heart hypertrophy and improved hemodynamic function. In addition, distal pulmonary capillaries were preserved in the Piezo1-knockout mice, associated with a lower number of senescent endothelial cells.
This study provides evidence that Piezo1 expressed in PASMCs is critically involved in the pathogenesis of PH by controlling pulmonary vascular tone, arterial remodeling, and associated lung capillary rarefaction due to endothelial cell senescence.
肺动脉高压（PH）是一种危及生命、进行性发展且无法治愈的疾病。PH的特征包括：（1）肺动脉平滑肌细胞（PASMCs）持续收缩；（2）肺动脉平滑肌细胞过度增殖。在PH发展过程中，PASMCs所面临的一个主要刺激是机械应力改变，其源于血压升高、血流速度变化以及肺动脉逐渐僵硬。机械敏感离子通道，包括Piezo1（压电型机械敏感离子通道组分-1），可感知这种机械刺激并将其转化为多种细胞反应，包括收缩性或增殖。因此，本研究的目的是阐明Piezo1在PASMCs中对PH发展和进展的具体作用。
通过以下方式评估Piezo1在PH中的细胞类型特异性功能：（1）来自PH患者的PASMCs和肺组织；（2）两种以平滑肌细胞特异性、条件性Piezo1基因敲除为特征的小鼠品系。利用这些品系，在分离、灌注和通气的小鼠肺、线肌张力测定和增殖试验中评估Piezo1在PH发展和进展中的平滑肌细胞特异性作用。最后，通过对这些小鼠诱导慢性缺氧性PH，深入了解肺血管细胞衰老情况，评估平滑肌细胞特异性Piezo1基因敲除的体内功能。
与健康对照相比，PH患者的PASMCs表现出Piezo1表达升高和增殖表型增加。通过定量实时聚合酶链反应和膜片钳记录证实，平滑肌细胞特异性Piezo1缺失可防止小鼠缺氧诱导的PASMC增殖增加。此外，Piezo1基因敲除降低了分离、灌注和通气小鼠肺、去内皮肺动脉中的缺氧性肺血管收缩以及体内血流动力学测量值。因此，基因敲除小鼠在很大程度上受到保护，免受慢性缺氧诱导的PH发展影响，右心室肥厚得到改善，血流动力学功能得到改善。此外，Piezo1基因敲除小鼠的远端肺毛细血管得以保留，与衰老内皮细胞数量减少有关。
本研究提供了证据表明，PASMCs中表达的Piezo1通过控制肺血管张力、动脉重塑以及由于内皮细胞衰老导致的相关肺毛细血管稀疏，在PH发病机制中起关键作用。
