Smooth muscle cell Piezo1 is essential for phenotypic switch and neointimal hyperplasia

Disturbed blood flow is a critical factor in activation of vascular smooth muscle cells (VSMCs) and initiation of neointimal hyperplasia. The Piezo1 channel is a recent yet well-characterised mechanosensor that plays a vital role in vascular development and homeostasis. However, the role of VSMC Piezo1 in neointima development remains largely unknown. The purpose of this study is to investigate the functional role of Piezo1 channel in neointimal hyperplasia. We measured the expression of Piezo1 in VSMC-rich neointima from human coronary artery samples and two mouse neointimal hyperplasia models which were induced by cast implantation or guidewire injury. We utilised VSMC-specific Piezo1 knockout mice to explore its function and the underlying mechanism of neointimal hyperplasia, both in vivo and in vitro. In human and mouse neointima samples, we observed a significant up-regulation of Piezo1 expression in the VSMC-rich neointima compared to the medial layer. VSMC-specific knockout of Piezo1 significantly reduced neointimal hyperplasia in both animal models. Activation of Piezo1 facilitates, whereas Piezo1 deficiency inhibits disturbed flow-induced cell proliferation, migration and synthetic phenotype switch. Mechanistic studies suggest that Piezo1 activates YAP and TAZ through Ca2+ and its downstream effectors calmodulin kinase II and calcineurin, which in turn drive VSMC proliferation and migration, thereby facilitating neointimal hyperplasia. These findings demonstrate a critical role of mechanosensitive Piezo1 channel in neointimal hyperplasia via modulating VSMC phenotype. Piezo1 channels may represent a novel therapeutic target for maladaptive vascular remodelling and occlusive vascular diseases.