Endothelial upregulation of mechanosensitive channel Piezo1 in pulmonary hypertension

Ziyi Wang, Jiyuan Chen, Aleksandra Babicheva, Pritesh P. Jain, Marisela Rodriguez, Ramon J. Ayon, Keeley S. Ravellette, Linda Wu, Francesca Balistrieri, Haiyang Tang, Xiaomin Wu, Tengteng Zhao, Stephen M. Black, Ankit A. Desai, Joe G.N. Garcia, Xin Sun, John Y.J. Shyy, Daniela Valdez-Jasso, Patricia A. Thistlethwaite, Ayako MakinoJian Wang, Jason X.J. Yuan

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Piezo is a mechanosensitive cation channel responsible for stretch-mediated Ca2 þ and Na þ influx in multiple types of cells. Little is known about the functional role of Piezo1 in the lung vasculature and its potential pathogenic role in pulmonary arterial hypertension (PAH). Pulmonary arterial endothelial cells (PAECs) are constantly under mechanic stretch and shear stress that are sufficient to activate Piezo channels. Here, we report that Piezo1 is significantly upregulated in PAECs from patients with idiopathic PAH and animals with experimental pulmonary hypertension (PH) compared with normal controls. Membrane stretch by decreasing extracellular osmotic pressure or by cyclic stretch (18% CS) increases Ca2 þ -dependent phosphorylation (p) of AKT and ERK, and subsequently upregulates expression of Notch ligands, Jagged1/2 (Jag-1 and Jag-2), and Delta like-4 (DLL4) in PAECs. siRNA-mediated downregulation of Piezo1 significantly inhibited the stretch-mediated pAKT increase and Jag-1 upregulation, whereas downregulation of AKT by siRNA markedly attenuated the stretch-mediated Jag-1 upregulation in human PAECs. Furthermore, the mRNA and protein expression level of Piezo1 in the isolated pulmonary artery, which mainly contains pulmonary arterial smooth muscle cells (PASMCs), from animals with severe PH was also significantly higher than that from control animals. Intraperitoneal injection of a Piezo1 channel blocker, GsMTx4, ameliorated experimental PH in mice. Taken together, our study suggests that membrane stretch-mediated Ca2 þ influx through Piezo1 is an important trigger for pAKT-mediated upregulation of Jag-1 in PAECs. Upregulation of the mechanosensitive channel Piezo1 and the resultant increase in the Notch ligands (Jag-1/2 and DLL4) in PAECs may play a critical pathogenic role in the development of pulmonary vascular remodeling in PAH and PH.

Original languageEnglish (US)
Pages (from-to)C1010-C1027
JournalAmerican Journal of Physiology - Cell Physiology
Volume321
Issue number6
DOIs
StatePublished - Dec 2021

Keywords

  • Calcium signaling
  • Mechanosensation
  • Membrane stretch
  • Novel channels
  • Pulmonary artery

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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