Abstract 4138639: Exploring advanced therapeutic approaches for atherosclerosis: Targeting efferocytosis and EndoMT with a focus on the CD47

Background: The anti-phagocytic molecule CD47 is upregulated in the atherosclerotic plaques of patients with cerebrovascular disease; however, the molecular mechanisms responsible for the development and progression of atherosclerotic lesions have not been fully established. In this study, we postulate how endothelial-specific CD47 promotes endothelial-to-mesenchymal transition (EndoMT) in potentiating atherosclerosis and assess the efficacy of the development of novel therapeutic interventions for cardiovascular disease. Methods: Using single-cell RNA sequencing (scRNA-seq), combined with molecular, cellular, and biochemical analyses, we investigated the role of endothelial CD47 in stimulating EndoMT using knock-out in ApoE-/- atherosclerotic mouse models. Results: ScRNA-seq revealed that CD47 promotes EndoMT, and the loss of endothelial CD47 inhibits EndoMT marker expression as well as transforming growth factor-beta signaling in vitro and atherosclerotic mice, which is associated with smaller lesions in Apoe-/- mouse model. In endothelial cells, CD47 hinders efferocytosis of senescent ECs and represses macrophage’s efferocytotic capacity to propel arterial inflammation and atherogenesis. Mechanistically, the interaction between CD47 and efferocytic receptor MerTK exacerbates inflammation by inhibiting the process of efferocytosis in endothelial cells and macrophages under atherogenic conditions. In response to atherogenic stimuli, endothelial CD47 upregulates the endocytic adaptor protein epsin, causing fibroblast growth factor receptor-1 (FGFR1) signal attenuation that upregulates TGF-β signaling and promoting EndoMT and potentiating atherosclerosis. Conclusion: We conclude that endothelial CD47 potentiates EndoMT during atherogenesis by increasing TGF-β signaling through FGFR1 internalization and degradation and targeted manipulating CD47 expression with precision nanomedicine offering a novel approach for mitigating cardiovascular disease.