Enhanced Yoda1-induced vasoconstriction in pulmonary arterial smooth muscle from monocrotaline-induced pulmonary hypertensive rats.

Mechanical forces such as shear stress, stretch, and pressure play critical roles in regulating vascular function. Mechanosensitive ion channels convert these mechanical stimuli into cytosolic Ca2+ signals that modulate vascular tone. The Piezo family of mechanosensitive channels, comprising Piezo1 and Piezo2, consists of Ca2+-permeable ion channels activated by mechanical stress. Piezo1 is predominantly expressed in non-neuronal cells, whereas Piezo2 is mainly localized to sensory neurons and mechanosensory tissues. The present study investigated the contribution of Piezo1 channels to vasoconstriction using Yoda1, a selective Piezo1 activator, in human pulmonary arterial smooth muscle cells (PASMCs) and rat pulmonary arterial smooth muscle (PASM) tissues. Both Piezo1 and Piezo2 expression levels were upregulated in PASMCs from patients with pulmonary arterial hypertension (PAH) and in PASMs from monocrotaline (MCT)-induced PAH rats. Yoda1 elicited Piezo1-mediated ionic currents in PAH-PASMCs, which were inhibited by GsMTx4, a blocker of Piezo1/2 channels. Yoda1 also increased cytosolic Ca2+ concentration in a concentration-dependent manner, with significantly larger responses in PAH-PASMCs than in normal PASMCs. Furthermore, Yoda1 induced stronger vasoconstriction in PASM tissues from MCT-PAH rats than in those from control rats. These findings strongly suggest that upregulated Piezo1 expression enhances vasoconstriction in PASMs from experimental PAH models, thereby contributing to PAH progression. Piezo1 channels may therefore represent a promising therapeutic target for pulmonary vascular diseases such as PAH.