Endothelial upregulation of mechanosensitive channel Piezo1 in pulmonary hypertension

Am J Physiol Cell Physiol. 2021 Dec 1;321(6):C1010-C1027. doi: 10.1152/ajpcell.00147.2021. Epub 2021 Oct 20.


Piezo is a mechanosensitive cation channel responsible for stretch-mediated Ca2+ and Na+ 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+-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+ 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.

Keywords: calcium signaling; mechanosensation; membrane stretch; novel channels; pulmonary artery.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Cells, Cultured
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Female
  • Humans
  • Hypertension, Pulmonary / metabolism*
  • Hypertension, Pulmonary / pathology
  • Indoles / pharmacology
  • Ion Channels / biosynthesis*
  • Male
  • Mechanotransduction, Cellular / drug effects
  • Mechanotransduction, Cellular / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Pulmonary Artery / drug effects
  • Pulmonary Artery / metabolism*
  • Pulmonary Artery / pathology
  • Pyrroles / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Up-Regulation / drug effects
  • Up-Regulation / physiology*


  • Indoles
  • Ion Channels
  • PIEZO1 protein, human
  • Pyrroles
  • Semaxinib