Piezo1 Agonist Yoda1 Induces Rapid Relaxation in Cultured Airway Smooth Muscle Cells and Bronchodilation in Mouse Models.

Abstract

Bronchodilators that relax airway smooth muscle cells (ASMCs) are essential for treating constrictive airway diseases such as asthma. However, the existing bronchodilators are often unable to control symptoms of severe asthmatic patients, leaving a pressing need to search for alternatives. Recent studies indicate that the transmembrane mechanosensitive channel, Piezo1 may provide a novel target for bronchodilation as it mediates ASMCs relaxation via calcium signaling and activation of large-conductance calcium-activated potassium channels (BK_Ca), and Piezo1 specific agonist Yoda1 has been shown to reduce cell stiffness and traction force in cultured ASMCs after 24 h incubation. Thus in this study, we further explored the potential of Yoda1 for inducing rapid ASMCs relaxation and bronchodilation. We treated either cultured ASMCs or allergen-induced mouse models of asthma with Yoda1 at various doses, and then assessed the resulting variations in cell stiffness, traction force, and molecular signaling of cultured ASMCs, as well as in airway resistance of the mouse models. We found that exposure to Yoda1 rapidly decreased cell stiffness, traction force in association with induced calcium signaling and BK_Ca activation in cultured ASMCs, and reduced airway resistance in methacholine-challenged mice in a dose-dependent manner. These results indicate that chemical activation of Piezo1 with specific agonist Yoda1 was indeed capable of inducing bronchodilation by relaxing ASMCs, and thus provide insights into development of Piezo1 agonist-based novel bronchodilators for treating constrictive airway disorders such as asthma.