Wei Feng, Lin Ziying, Lu Wenju, Luo Haiyun, Feng Huazhuo, Liu Shiyun, Zhang Chenting, Zheng Yulin, Chen Jiyuan, Mo Shaocong, Wang Chen, Zhang Zizhou, Feng Wei, Zhu Junqi, Yang Qifeng, Du Min, Kong Weiguo, Liu Aofeng, Lai Jiaxuan, Li Xiang, Wu Xuefen, Lai Ning, Chen Yuqin, Yang Kai, Wang Jian
State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital (F.W., Z.L., W.L., H.L., H.F., S.L., C.Z., Y.Z., S.M., C.W., Z.Z., W.F., J.Z., Q.Y., M.D., W.K., A.L., J.L., X.L., X.W., N.L., Y.C., K.Y., J.W.), Guangzhou Medical University, China.
Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China (J.C.).
Hypertension. 2025 Apr;82(4):583-597. doi: 10.1161/HYPERTENSIONAHA.124.22948. Epub 2025 Jan 6.
Mechanosensitive Piezo1 (Piezo Type Mechanosensitive Ion Channel Component 1) channel plays a key role in pulmonary hypertension (PH). However, the role of Piezo2 in PH remains unclear.
Endothelial cell (EC)-specific Piezo2 knockout (, Tek-Cre; ) rats and primarily cultured pulmonary microvascular ECs were used to determine the role of Piezo2 in PH.
Data analysis of publicly accessible single-cell RNA-sequencing data sets uncovered significant downregulation of Piezo2 in lung ECs from patients with idiopathic pulmonary arterial hypertension, which was verified in the lungs/ECs from PH rat models induced by hypoxia or monocrotaline. Comparing to wild-type rats, rats exhibited exacerbated PH in both hypoxia-induced PH and monocrotaline-induced PH, characterized by the worsened hemodynamical and histological changes. rats showed dramatic loss of pulmonary microvessels, in association with the decreased intracellular free calcium concentration ([Ca]) and downregulation of VEGFR2 (vascular endothelial growth factor receptor 2) and phosphorylated SRF (serum response factor) in pulmonary microvascular ECs. Knockout of Piezo2 or treatment with a calcium chelator, EDTA, impaired the ability of tube formation and migration in pulmonary microvascular ECs, which was restored by supplementation of extra calcium. A safflower oil diet rich in linoleic acid, which can enhance the stability and function of Piezo2, effectively alleviated PH development in a hypoxia-induced PH rat model.
This study demonstrates that EC-specific knockout of Piezo2 exacerbates PH pathogenesis, at least partially, through the suppression of [Ca]/phosphorylated SRF/VEGFR2 signaling axis in pulmonary vascular ECs. Targeted activation of Piezo2 could be a novel effective strategy for the treatment of PH.
机械敏感离子通道Piezo1（压电型机械敏感离子通道组分1）在肺动脉高压（PH）中起关键作用。然而，Piezo2在PH中的作用仍不清楚。
采用内皮细胞（EC）特异性Piezo2基因敲除（Tek-Cre；）大鼠和原代培养的肺微血管内皮细胞来确定Piezo2在PH中的作用。
对公开可用的单细胞RNA测序数据集进行数据分析发现，特发性肺动脉高压患者肺内皮细胞中Piezo2显著下调，这在缺氧或野百合碱诱导的PH大鼠模型的肺/内皮细胞中得到验证。与野生型大鼠相比，在缺氧诱导的PH和野百合碱诱导的PH中均表现出PH加重，其特征为血流动力学和组织学变化恶化。大鼠肺微血管显著减少，同时肺微血管内皮细胞内游离钙浓度（[Ca]）降低、血管内皮生长因子受体2（VEGFR2）和磷酸化血清反应因子（SRF）下调。敲除Piezo2或用钙螯合剂EDTA处理会损害肺微血管内皮细胞的管形成和迁移能力，补充额外的钙可恢复该能力。富含亚油酸的红花油饮食可增强Piezo2的稳定性和功能，能有效减轻缺氧诱导的PH大鼠模型中的PH发展。
本研究表明，EC特异性敲除Piezo2至少部分通过抑制肺血管内皮细胞中的[Ca]/磷酸化SRF/VEGFR2信号轴而加剧PH发病机制。靶向激活Piezo2可能是治疗PH的一种新型有效策略。
