4.7 Article

Endothelial upregulation of mechanosensitive channel Piezo1 in pulmonary hypertension

Journal

AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 321, Issue 6, Pages C1010-C1027

Publisher

AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00147.2021

Keywords

calcium signaling; mechanosensation; membrane stretch; novel channels; pulmonary artery

Funding

  1. National Heart, Lung and Blood Institute of the National Institutes of Health [R35 HL135807, R01 HL146764]
  2. American Heart Association Postdoctoral Fellowship [20POST35210959]
  3. Science and Technology Planning Project of Guangzhou

Ask authors/readers for more resources

The upregulation of Piezo1 in PAH and PH may impact the cell signaling pathways in pulmonary arterial endothelial cells and smooth muscle cells, leading to pulmonary vascular remodeling, and the findings from the study provide new insights for potential therapeutic approaches.
Piezo is a mechanosensitive cation channel responsible for stretch-mediated Ca2 thorn and Na thorn 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 thorn -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 thorn 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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available