On April 5, 2021, Professor Wang Jian’s research team from the Pulmonary and Vascular Diseases Group of the State Key Laboratory of Respiratory Disease published a paper online entitled Upregulation of Piezo1 Enhances the Intracellular Free Calcium in Pulmonary Arterial Smooth Muscle Cells from Idiopathic Pulmonary Arterial Hypertension Patients (Top Journal of Medical District 1, Impact Factor: 7.713) in Hypertension (Original research). The study reveals the potential effect of the mechanosensitive (MS) ion channels Piezo1 on the regulation of calcium homeostasis in smooth muscle cells under normal conditions and pulmonary hypertension. The co-corresponding authors of this paper are Professor Wang Jian and Associate Professor Yang Kai from the Laboratory, and the co-first authors are 2018 postgraduate students Liao Jing, Professor Lu Wenju, and Dr. Chen Yuqin.

Pulmonary arterial hypertension (PAH) is a cardiopulmonary disease characterized by progressive increase in pulmonary artery pressures and pulmonary vascular resistance, which further damages the function of the right heart. Its pathophysiological characteristics mainly include abnormal contraction and remodeling of pulmonary blood vessels. The imbalance of Ca2+ homeostasis and Ca2+ overload in pulmonary artery smooth muscle cells (PASMCs) are important mechanisms that lead to abnormal contraction, proliferation and migration of PASMCs, which promotes pulmonary vasoconstriction and remodeling.

In recent years, the regulation of a new type of mechanosensitive (MS) ion channels Piezo1 on intracellular Ca2+ homeostasis has attracted widespread attention and is believed to play an important role in the pathogenesis of many cardiopulmonary and vascular diseases. Piezo1 is a mechanosensitive (MS) ion channel, which can be activated by fluid shear stress, mechanical tension or conformational changes caused by chemicals, and can mediate Ca2+ signals along the concentration gradient. It is still unclear whether and how Piezo1 participates in the regulation of calcium homeostasis of PAMSCs under PAH conditions, as well as the abnormal contraction, proliferation and migration of cells.

In this study, we first systematically defined the mechanism in which Piezo1 mediates Ca2+ homeostasis in PASMCs. We have observed that Piezo1 can mediate the increase of [Ca2+]i in PASMCs through two channels: (1) Piezo1 (Intra-Piezo1) located in subcellular organelles (including sarcoplasmic reticulum/endoplasmic reticulum, mitochondria and nuclear membrane) can mediate the release of intracellular Ca2+ beyond the regulation of IP3R and RyRs, and then trigger store-operated calcium entry inside the cell membrane. (2) PM-Piezo1 can mediate extracellular Ca2+ entry beyond the L-type voltage-dependent calcium channel (L-VDCC), store-operated calcium channel (SOCC) and caveolin-1. Then, through means like fluorescence live cell imaging, isolated aortic rings and cell proliferation, we further found that Piezo1 channel activation can mediate the contraction and proliferation of PASMCs. Finally, we found that compared to healthy control, Piezo1 expression and activity in PASMCs derived from patients with idiopathic PAH (IPAH) increased significantly, suggesting that the upregulation and activation of Piezo1 may be the important molecular mechanism of mediating the increase of [Ca2+]i in IPAH-PASMCs and inducing cell contraction and proliferation. Our results provide a more comprehensive definition for the subcellular activity and localization of Piezo1 in PASMCs, and provide new theories and ideas for calcium imbalance and homeostasis of PASMCs accompanied by PAH.

This study is funded by the National Natural Science Foundation of China, the Key R&D Program of the Ministry of Science and Technology, the Yangtze River Scholars Project of the Ministry of Education, the Local Innovative Scientific Research Team Project of the Pearl River Talent Plan of Guangdong Province, and the Natural Science Foundation of Guangdong Province.

On March 26, 2021, Professor Wang Jian’s research team from the Pulmonary Vascular Disease Group published an editorial online entitled NEDD9, a Hypoxia-upregulated Mediator for Pathogenic Platelet-endothelial Cell Interaction in Pulmonary Hypertension (Top Journal of Medical District 1, Impact Factor: 17.452). The first author of this editorial is Professor Wang Jian from the Laboratory, and the corresponding author is Professor Jason X.-J. Yuan from the University of California, San Diego.

This editorial summarizes the recent research progress and systematically discusses the possible molecular mechanisms of hypoxia up-regulated NEDD9 in pulmonary vascular endothelial cells and the mediation of platelet activation. The overexpression of NEDD9 in endothelial cells promotes the formation of pulmonary embolism and pulmonary vascular remodeling by mediating the increase in platelet/endothelial cell adhesion. Specific blocking of the adhesion between the two (for example: specific antibodies or pharmacological inhibitors) may be an effective means to inhibit in situ thrombosis and vascular remodeling, and to inhibit the occurrence and development of pulmonary hypertension, which needs further research and discussion.