Journal Article

High Shear Stress‐Induced Endothelial Piezo1 Downregulation Promotes Intracranial Aneurysm Formation via the PDGF‐BB/PDGFRβ Paracrine Signaling Pathway

Yang, Xiaohua, Zhu, Shijie, Tang, Haishuang, Li, Sisi, Xu, Fengfeng, Wang, Chuanchuan, Lu, Zhiwen, Huang, Qinghai

2025

Overview

Background Abnormally high shear stress (HSS) is strongly associated with intracranial aneurysm (IA) formation. Endothelial Piezo1 is sensitive to shear stress stimulation, but the mechanism by which it mediates this mechanobiological coupling process is unclear. Methods The correlation between shear stress and the Piezo1 expression was investigated using human IA samples and a parallel‐plate flow chamber system. To determine the effects of endothelial Piezo1 on the phenotype of neighboring vascular smooth muscle cells (VSMCs) and IA formation, the CRISPR/Cas9 system was used to inhibit endothelial Piezo1 gene expression in vitro. Piezo1ΔEC mice were produced by injecting AAV2‐BR1‐Tie2‐Cre into 8‐week‐old male Piezo1flox/flox mice, which were further used to construct the IA mouse model. Single‐cell RNA sequencing and intercellular communication analyses of co‐cultured endothelial cells (ECs) and VSMCs were used to screen for receptor‐ligand pairs after inhibiting EC Piezo1 in vitro. The role of the screened receptor‐ligand pair was further validated via in vivo and in vitro experiments. Additionally, the underlying mechanisms were investigated. Result Piezo1 expression correlated negatively with the shear stress in human IA. HSS reduced EC Piezo1 expression and promoted VSMC phenotypic transformation compared with physiological shear stress. Depletion of EC Piezo1 resulted in the VSMC phenotypic transformation and, more importantly, promoted aneurysmal vascular remodeling in the mouse IA model. The platelet‐derived growth factor subunit B (PDGFB)_Platelet‐derived growth factor receptor β (PDGFRβ) was identified as being involved in this process. Moreover, the PDGFRβ antagonist reversed the VSMC phenotypic transformation and attenuated IA progression. Mechanistically, Piezo1 depletion promoted PDGFB expression via YAP/β‐catenin pathway. Conclusion HSS downregulates Piezo1 expression in ECs, which subsequently enhances PDGF‐BB expression through the YAP/β‐catenin signaling pathway. The elevated PDGF‐BB facilitates phenotypic transition of VSMCs via PDGFRβ binding, ultimately contributing to IA formation. HSS downregulates Piezo1 expression in ECs, which subsequently enhances PDGF‐BB expression through the YAP/β‐catenin signaling pathway. The elevated PDGF‐BB facilitates phenotypic transition of VSMCs via PDGFRβ binding, ultimately contributing to IA formation.

• Publisher: John Wiley & Sons, Inc
• Subject: Aneurysm / Aneurysms / Animals / Becaplermin - metabolism / Blood vessels / Catenin / Cell interactions / Cells, Cultured / Collagen / CRISPR / Down-regulation / Down-Regulation - physiology / Endothelial cells / Endothelial Cells - metabolism / Extracellular matrix / Fluid dynamics / Gene expression / Genes / Genetic transformation / Growth factors / Hemodynamics / Humans / intracranial aneurysm / Intracranial Aneurysm - metabolism / Intracranial Aneurysm - pathology / Ion Channels - biosynthesis / Ion Channels - genetics / Ion Channels - metabolism / Kinases / Ligands / Male / Mechanical stimuli / Mice / Mice, Inbred C57BL / Mice, Transgenic / Muscle, Smooth, Vascular - metabolism / Paracrine Communication - physiology / Paracrine signalling / Penicillin / phenotype transformation / Phenotypes / Physiology / Piezo1 / Platelet-derived growth factor / Platelets / platelet‐derived growth factor subunit BB (PDGF‐BB) / Proto-Oncogene Proteins c-sis - metabolism / Receptor, Platelet-Derived Growth Factor beta - metabolism / Shear stress / Signal transduction / Signal Transduction - physiology / Smooth muscle / Stress, Mechanical / Veins & arteries / Yes-associated protein