SPARC modulates macrophage-like phenotype transformation in VSMCs and triggers a vicious cycle

Intracranial aneurysms (IAs) are characterized by abnormal cerebral artery dilations and pose significant risks due to their potential for rupture, leading to subarachnoid hemorrhage. Although inflammation and vascular smooth muscle cell (VSMC) phenotypic transformations are implicated in IA pathogenesis, the role of secreted protein acidic and rich in cysteine (SPARC) in these processes remains poorly understood. This study explored the role of SPARC in inducing macrophage-like phenotypic transformation of VSMCs using data from the Gene Expression Omnibus (GEO) database and in vitro experiments. SPARC overexpression in VSMCs was induced, and its effects on VSMC phenotype markers, reactive oxygen species (ROS) production, macrophage chemotaxis, and lipid accumulation were evaluated. Additionally, molecular docking was used to explore the potential interaction between SPARC and aspirin. SPARC overexpression induced a shift from contractile to macrophage-like and pro-inflammatory VSMC phenotypes, which was associated with elevated ROS production. ROS inhibition blocked this transformation. SPARC also upregulated markers related to macrophage-like behavior and enhanced VSMC migration. Furthermore, molecular docking revealed potential binding of aspirin to SPARC, and aspirin treatment mitigated macrophage-like VSMC transformation in a TNF-α-induced IA model. SPARC promotes macrophage-like transformation in VSMCs through ROS production, contributing to IA pathogenesis. Targeting SPARC or ROS may offer therapeutic strategies for preventing IA rupture. Aspirin's potential to regulate SPARC expression opens new avenues for IA treatment.