Endothelial upregulation of mechanosensitive channel Piezo1 in pulmonary hypertension

Abstract

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 to 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 (Jag1 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, while downregulation of AKT by siRNA markedly attenuated the stretch-mediated Jag1 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. 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.

Mechanically activated ion channel Piezo1 contributes to melanoma malignant progression through AKT/mTOR signaling

“… 33 Additionally, membrane stretch-mediated Ca2+ influx through Piezo1 is an important trigger for phosphorylation of AKT mediated upregulation of pulmonary arterial endothelial cells. 34 Thus, in contrast to our results, intracellular Ca2+ may be regulate the AKT pathway in part via Piezo1 in melanoma cells.…”

Ca2+ Signalling and Hypoxia/Acidic Tumour Microenvironment Interplay in Tumour Progression

“…Moreover, hypo-osmotic conditions upregulated Piezo1 protein levels in the same cells and promoted the activation of Akt and Erk signalling pathways via Piezo1-induced Ca 2+ entry, as demonstrated by siPiezo1 treatment, with downstream upregulation of Notch ligands [96]. The potential therapeutic effect of Piezo1 blockade in the mouse model with chronic hypoxia-induced PH was assessed by GsMTx4 treatment, which partially reduced the chronic hypoxia-induced PH [96]. These data support the role of Piezo1 in the remodelling of the pulmonary vasculature in PH.…”

“…Human pulmonary arterial endothelial cells showed maximal Piezo1 expression at 6 h hypoxic exposure, with a consequent increase in calpain-1 and calpain-2, both involved in PAH development [96]. Moreover, hypo-osmotic conditions upregulated Piezo1 protein levels in the same cells and promoted the activation of Akt and Erk signalling pathways via Piezo1-induced Ca 2+ entry, as demonstrated by siPiezo1 treatment, with downstream upregulation of Notch ligands [96]. The potential therapeutic effect of Piezo1 blockade in the mouse model with chronic hypoxia-induced PH was assessed by GsMTx4 treatment, which partially reduced the chronic hypoxia-induced PH [96].…”

“…Recent works have shown that Piezo1 is upregulated in pulmonary arterial endothelial cells of patients with pulmonary arterial hypertension (PAH) and in pulmonary artery smooth muscle cells of mice and rats models with experimental chronic hypoxia-induced pulmonary hypertension (PH) [95,96]. Human pulmonary arterial endothelial cells showed maximal Piezo1 expression at 6 h hypoxic exposure, with a consequent increase in calpain-1 and calpain-2, both involved in PAH development [96].…”

“…Recent works have shown that Piezo1 is upregulated in pulmonary arterial endothelial cells of patients with pulmonary arterial hypertension (PAH) and in pulmonary artery smooth muscle cells of mice and rats models with experimental chronic hypoxia-induced pulmonary hypertension (PH) [95,96]. Human pulmonary arterial endothelial cells showed maximal Piezo1 expression at 6 h hypoxic exposure, with a consequent increase in calpain-1 and calpain-2, both involved in PAH development [96]. Moreover, hypo-osmotic conditions upregulated Piezo1 protein levels in the same cells and promoted the activation of Akt and Erk signalling pathways via Piezo1-induced Ca 2+ entry, as demonstrated by siPiezo1 treatment, with downstream upregulation of Notch ligands [96].…”