Alveolar stretch activation of endothelial Piezo1 protects adherens junctions and lung vascular barrier

Research output: Contribution to journalArticle

Authors

  • Ming Zhong
  • Wei Wu
  • Hojin Kang
  • Zhigang Hong
  • Shiqin Xiong
  • Xiaopei Gao
  • Jalees Rehman
  • Yulia A. Komarova
  • Asrar B. Malik

External Institution(s)

  • University of Illinois at Chicago
  • Fudan University

Details

Original languageEnglish (US)
Pages (from-to)168-177
Number of pages10
JournalAmerican journal of respiratory cell and molecular biology
Volume62
Issue number2
StatusPublished - Jan 1 2020
Peer-reviewedYes

Abstract

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 (Piezo1iEC2/2), 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 Piezo1iEC2/2 mice as compared with control Piezo1fl/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 Piezo1iEC2/2 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.

    Research areas

  • Alveolar stretch, Calcium signaling, Mechanotransduction

Citation formats

APA

Zhong, M., Wu, W., Kang, H., Hong, Z., Xiong, S., Gao, X., ... Malik, A. B. (2020). Alveolar stretch activation of endothelial Piezo1 protects adherens junctions and lung vascular barrier. American journal of respiratory cell and molecular biology, 62(2), 168-177. https://doi.org/10.1165/rcmb.2019-0024OC

Harvard

Zhong, M, Wu, W, Kang, H, Hong, Z, Xiong, S, Gao, X, Rehman, J, Komarova, YA & Malik, AB 2020, 'Alveolar stretch activation of endothelial Piezo1 protects adherens junctions and lung vascular barrier', American journal of respiratory cell and molecular biology, vol. 62, no. 2, pp. 168-177. https://doi.org/10.1165/rcmb.2019-0024OC