Mechanosensitive channel Piezo1 is required for pulmonary artery smooth muscle cell proliferation

Abstract

Concentric pulmonary vascular wall thickening due partially to increased PASMC proliferation contributes to elevating PVR in patients with pulmonary hypertension (PH). While pulmonary vasoconstriction may be an early contributor to increasing PVR, the transition of contractile PASMCs to proliferative PASMCs may play an important role in the development and progression of pulmonary vascular remodeling in PH. A rise in cytosolic Ca2+ concentration ([Ca2+]cyt) is a trigger for PASMC contraction and proliferation. Here we report that upregulation of Piezo1, a mechanosensitive cation channel, is involved in the contractile-to-proliferative phenotypic transition of PASMCs and development of pulmonary vascular remodeling. By comparing freshly isolated PA (contractile PASMCs) and primary cultured PASMCs in growth medium (proliferative PASMCs), we found that Piezo1, Notch2/3 and CaSR protein levels were significantly higher in proliferative PASMCs than in contractile PASMCs. Upregulated Piezo1 was associated with an increase in expression of PCNA, a marker for cell proliferation, whereas downregulation (with siRNA) or inhibition (with GxMTx4) of Piezo1 attenuated PASMC proliferation. Furthermore, Piezo1 in the remodeled PA from rats with experimental PH was upregulated in comparison to PA from control rats. These data indicate that PASMC contractile-to-proliferative phenotypic transition is associated with the transition or adaptation of membrane channels and receptors. Upregulated Piezo1 may play a critical role in PASMC phenotypic transition and PASMC proliferation. Upregulation of Piezo1 in proliferative PASMCs may likely be required to provide sufficient Ca2+ to assure nuclear/cell division and PASMC proliferation, contributing to the development and progression of pulmonary vascular remodeling in PH.

The mechanosensitive Piezo1 channels contribute to the arterial medial calcification

“…Higher expression was detected in resistance arteries and lower expression in conduit arteries, with an increasing trend in the distal direction within each section ( Retailleau et al, 2015 ). Their function can also show regional differences due to, among others, the difference in pressure in the given section (systemic vs pulmonary circulations) ( Chen et al, 2022 ). Therefore, the extent of their contribution to the elevation of intracellular calcium concentration, and so, to the calcification can also vary ( Badin et al, 2022 ).…”

Piezo1, a novel therapeutic target to treat pulmonary arterial hypertension

“…Additionally, it has been shown that effective knockdown of Piezo1 attenuated the FBS-induced proliferation of human PASMC ( Maneshi et al, 2018 ) and inhibited the FBS-induced proliferation of human PASMC ( Liao et al, 2021 ). Also, previous study ( Chen et al, 2022 )have shown that Piezo1 is required for pulmonary artery smooth muscle cell proliferation. Expression of Piezo1 is increased in the pulmonary artery endothelial cells of patients with idiopathic pulmonary artery hypertension and experimental PH ( Wang et al, 2021 ) .…”

Chemical Activation of Piezo1 Alters Biomechanical Behaviors toward Relaxation of Cultured Airway Smooth Muscle Cells

“…It has been reported that contractile and proliferative smooth muscles may have different Piezo1 expressions. 34) In this study, we mainly used cultured proliferative ASMCs. To test whether contractile ASMCs in vivo also express Piezo1, we compared the Piezo1 mRNA expression in freshly isolated ASMCs (P0, contractile phenotype), and cultured cells (proliferative phenotype) in the passage of 5 (P5) and P10.…”