Mechanosensor Piezo1‑mediated smooth muscular cell pyroptosis contributes to vascular calcification.

Abstract

Vascular calcification is a pathological consequence of chronic inflammation and phenotypic switching in smooth muscle cells (SMCs). However, the mechanisms underlying vascular calcification remain unclear. The present study explores the role of the mechanosensor channel, Piezo1, in regulating vascular SMC (VSMC) death and vascular calcification. The findings of the present study demonstrated that Piezo1 expression is upregulated in the atherosclerotic plaques of both mice and patients. In vitro experiments revealed that calcifying medium (CM) induced an increase in Piezo1 and runt‑related transcription factor 2 (RUNX2) expression, triggered pyroptosis in cultured VSMCs and promoted calcium deposition in arterial rings. These effects were mitigated by a Piezo1 inhibitor and exacerbated by a Piezo1 agonist. Furthermore, gene deletion of NLR family pyrin domain containing 3 (NLRP3), caspase1 or gasdermin D also reduced CM‑induced pyroptosis and calcium deposition in VSMCs. Immunoprecipitation assays showed that calcium/calmodulin dependent protein kinase II (CaMKII), a downstream effector of Piezo1, interacted with RUNX2, and CaMKII inhibition attenuated both pyroptosis and calcification in VSMCs exposed to CM. The role of Piezo1 in mediating VSMC pyroptosis and vascular calcification was confirmed in a mouse model, where VSMC‑specific deletion of Piezo1 inhibited arterial calcification in chronic kidney disease. In conclusion, Piezo1 is a key regulator of vascular calcification via Ca2+‑CaMKII‑mediated activation of the NLRP3 inflammasome and subsequent VSMC pyroptosis.