| First Author | Zhong M | Year | 2020 |
| Journal | Am J Respir Cell Mol Biol | Volume | 62 |
| Issue | 2 | Pages | 168-177 |
| PubMed ID | 31409093 | Mgi Jnum | J:301661 |
| Mgi Id | MGI:6504056 | Doi | 10.1165/rcmb.2019-0024OC |
| Citation | Zhong M, et al. (2020) Alveolar Stretch Activation of Endothelial Piezo1 Protects Adherens Junctions and Lung Vascular Barrier. Am J Respir Cell Mol Biol 62(2):168-177 |
| abstractText | Disruption of alveolar-capillary barriers is a major complication of high-volume mechanical ventilation referred to as "ventilator-induced lung injury." The stretching force in alveoli is transmitted to endothelial cells, increasing the tension on underlying endothelial plasma membrane. The mechanosensor Piezo1, a plasma membrane cation channel, was inducibly deleted in endothelial cells of mice (Piezo1(iEC-/-)), which allowed us to study its role in regulating the endothelial barrier response to alveolar stretch. We observed significant increase in lung vascular permeability in Piezo1(iEC-/-) mice as compared with control Piezo1(fl)(/fl) mice in response to high-volume mechanical ventilation. We also observed that human lung endothelial monolayers depleted of Piezo1 and exposed to cyclic stretch had increased permeability. We identified the calcium-dependent cysteine protease calpain as a downstream target of Piezo1. Furthermore, we showed that calpain maintained stability of the endothelial barrier in response to mechanical stretch by cleaving Src kinase, which was responsible for disassembling endothelial adherens junctions. Pharmacological activation of calpain caused Src cleavage and thereby its inactivation, and it restored the disrupted lung endothelial barrier seen in Piezo1(iEC-/-) mice undergoing high-volume mechanical ventilation. Our data demonstrate that downregulation of Piezo1 signaling in endothelium is a critical factor in the pathogenesis of ventilator-induced lung injury, and thus augmenting Piezo1 expression or pharmacologically activating Piezo1 signaling may be an effective therapeutic strategy. |
