PIEZO1 regulates smooth muscle cell plasticity by integrating mechanical stretch with glycolytic metabolism

Aims: Pulmonary artery smooth muscle cells (PASMCs) sense and respond to constant mechanical strain, which is vital for lung homeostasis and disease. Mechanical stimuli and altered glycolytic metabolism are intrinsically intertwined in proliferative PASMCs undergoing a phenotypic switching, however, it remains unclear how biophysical forces and glycolysis are coupled in PASMCs. We report that PIEZO1 plays a critical role in PASMC metabolism and distinguishable mechanical cues differently rewire PIEZO1-mediated signalling into pro- and anti-glycolytic metabolism. Methods and results: Under hypoxia, activation of PIEZO1 promotes glycolysis in PASMCs through HIF1α and PFKFB3, resulting in profound lactate production and cell proliferation. In severe pulmonary injury induced by bleomycin, PIEZO1 is hyper-activated, which led to PPARγ activation, thereby antagonizing TGFβ signalling and restraining glycolysis and proliferation via FBP1. Loss of smooth muscle Piezo1 attenuates pneumonectomy and hypoxia induced PASMC growth and vascular remodelling, while aggravates pulmonary fibrosis in mice. Conclusion: Our study reveals that PIEZO1-mediated mechano-metabolic coupling contributes to PASMCs plasticity. This discovery identified an intrinsic mechanism that integrates mechanical stretch with cellular glycolysis during pulmonary vascular remodelling.