GRIA2/ENPP3 Regulates the Proliferation and Migration of Vascular Smooth Muscle Cells in the Restenosis Process Post-PTA in Lower Extremity Arteries

Abstract

Restenosis is the main restriction on the long-term efficacy of percutaneous transluminal angioplasty (PTA) therapy for peripheral artery disease (PAD). Interventions to prevent restenosis are poor, and the exact mechanism is unclear. Here, we aimed to elucidate the role of <i>GRIA2</i> in the restenosis process post-PTA in lower extremity arteries. We searched the differentially expressed genes (DEGs) between atherosclerotic and restenotic artery plaques in the Gene Expression Omnibus (GEO), and five DEGs were identified. Combined with Gene Ontology (GO) enrichment analysis, <i>GRIA2</i> was significantly correlated with the restenosis process. Tissue samples were used to examine <i>GRIA2</i> expression by immunofluorescence staining of atherosclerotic and restenotic artery plaques. The regulation of <i>GRIA2</i> in vascular smooth muscle cells (VSMCs) was confirmed by lentiviral transfection. Overexpression of <i>GRIA2</i> promoted the proliferation and migration of VSMCs. Using Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and protein-protein interaction (PPI) network, a strong connection between <i>ENPP3</i> and <i>GRIA2</i> was discovered. <i>In vitro</i> results showed that the high expression of <i>GRIA2</i> in VSMCs enhanced the expression of <i>ENPP3</i>, while downregulation of <i>GRIA2</i> downregulated <i>ENPP3</i>. <i>GRIA2</i> is highly differentially expressed in restenotic arterial plaques, promoting the proliferation and migration of VSMCs through upregulation of <i>ENPP3</i>. These discoveries will help us to obtain a better understanding of restenosis in lower extremity arteries.