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 of Guangzhou Medical University, Guangzhou, Guangdong, China; Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, CA, USA.
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 of Guangzhou Medical University, Guangzhou, Guangdong, China; Inner Mongolia People's Hospital Key Laboratory of National Health Commission for the Diagnosis & Treatment of COPD, Hohhot, Inner Mongolia, China.
Thromb Res. 2022 Oct;218:52-63. doi: 10.1016/j.thromres.2022.08.006. Epub 2022 Aug 17.
Piezo1 is an important mechanosensitive channel implicated in vascular remodeling. However, the role of Piezo1 in different types of vascular cells during the development of pulmonary hypertension (PH) induced by high shear stress is largely unknown.
We used a rat PH model established by left pulmonary artery ligation (LPAL, for 2-5 weeks), which mimics the high flow and hemodynamic stress, to study Piezo1 contribution to pulmonary vascular remodeling.
Right ventricular systolic pressure (RVSP), a surrogate measure for pulmonary arterial systolic pressure, and right ventricular wall thickness, a measure for right ventricular hypertrophy, were significantly increased in LPAL rats compared with Sham-control (SHAM) rats. Rats in LPAL-5w groups developed remarkable pulmonary vascular remodeling, while phenylephrine-induced contraction and acetylcholine-induced relaxation were both significantly inhibited in these rats. Upregulation of Piezo1, in association with increase in cytosolic Ca concentration ([Ca]), was observed in pulmonary arterial smooth muscle cells (PASMCs) from LPAL-2w and LPAL-5w rats in comparison to the SHAM controls. Piezo1 upregulation in PASMCs from LPAL rats was directly related to Yes-associated protein (YAP)/ TEA domain transcription factor 4 (TEAD4). Piezo1 expression was also upregulated in the whole-lung tissue of LPAL rats. The endothelial upregulation of Piezo1 was related to transcriptional regulation by RELA (p65) and lung inflammation.
The upregulation of Piezo1 in both PASMCs and ECs coordinates with each other via different cell signaling pathways to cause pulmonary vascular remodeling in LPAL-PH rats, providing novel insights into the cell-type specific pathogenic roles of Piezo1 in shear stress-associated experimental PH.
Piezo1 是一种重要的机械敏感通道，参与血管重塑。然而，Piezo1 在高剪切应力诱导的肺动脉高压（PH）发展过程中不同类型血管细胞中的作用在很大程度上尚不清楚。
我们使用左肺动脉结扎（LPAL，2-5 周）建立的大鼠 PH 模型，模拟高流量和血流动力学应激，以研究 Piezo1 对肺血管重塑的贡献。
与 Sham-control（SHAM）大鼠相比，LPAL 大鼠的右心室收缩压（RVSP），肺动脉收缩压的替代指标，以及右心室壁厚度，右心室肥厚的指标，均显著升高。LPAL-5w 组大鼠出现明显的肺血管重塑，而这些大鼠的苯肾上腺素诱导收缩和乙酰胆碱诱导舒张均明显受到抑制。与 SHAM 对照组相比，LPAL-2w 和 LPAL-5w 大鼠的肺动脉平滑肌细胞（PASMCs）中 Piezo1 上调，同时细胞浆钙离子浓度（[Ca]）增加。LPAL 大鼠 PASMCs 中 Piezo1 的上调与 Yes 相关蛋白（YAP）/TEA 结构域转录因子 4（TEAD4）的上调直接相关。LPAL 大鼠的整个肺组织中 Piezo1 的表达也上调。LPAL 大鼠内皮细胞中 Piezo1 的上调与 RELA（p65）和肺炎症的转录调节有关。
PASMCs 和 ECs 中 Piezo1 的上调通过不同的细胞信号通路相互协调，导致 LPAL-PH 大鼠的肺血管重塑，为 Piezo1 在剪切应激相关实验性 PH 中的细胞类型特异性致病作用提供了新的见解。
