Neutrophil Extracellular Traps-Mediated Intraplaque Angiogenesis and Microvascular Permeability Promote Rapid Plaque Progression following Myocardial Infarction

Despite adherence to guideline-recommended therapies, survivors of myocardial infarction (MI) remain at high risk for recurrent ischemic events. This study aimed to elucidate the underlying mechanisms responsible for this residual risk. Using Mendelian randomization analysis and retrospective cohort study, we established a causal relationship between MI and plaque progression, potentially mediated by neutrophils. In a murine atherosclerotic model, MI precipitated a marked expansion in plaque volume accompanied by reduced stability; these pathological changes are consistent with the hallmark features of rapid plaque progression, which may trigger recurrent ischemic events. Pharmacological inhibition and adoptive transfer experiments using Padi4flox/floxLyz2Cre mice confirmed the pivotal role of neutrophils in MI-driven rapid plaque progression via neutrophil extracellular traps (NETs) formation. Further investigations revealed that NETs promote intraplaque hemorrhage by facilitating intraplaque angiogenesis and enhancing microvascular permeability, thereby exacerbating post-MI atherosclerotic inflammation. Mechanistically, bioinformatics analyses and in vitro experiments identified the transcription factor ETS proto-oncogene 1 as a critical regulator of NETs-mediated angiogenesis and endothelial permeability through the activation of the vascular endothelial growth factor A/vascular endothelial growth factor receptor 2 signaling pathway. In vivo pharmacological inhibition of ETS proto-oncogene 1 with TK216 markedly attenuated the rapid plaque progression after MI. In summary, this study provides the first comprehensive evidence that neutrophils and NETs drive rapid plaque progression following MI by modulating intraplaque angiogenesis and hemorrhage. These findings offer novel insights into the mechanisms underlying post-MI ischemic event recurrence and highlight promising therapeutic targets for clinical prevention.