Inhibition of bone morphogenetic protein 4 alleviates angiotensin II-induced abdominal aortic aneurysm by reducing inflammation and endothelial-mesenchymal transition

BACKGROUND AND AIMS: Abdominal aortic aneurysm (AAA) is one of the most common fatal macrovascular diseases worldwide which pathogenesis is still not well clarified. In this study, we systematically investigated the alternations of endothelial cell (ECs) functions and phenotypes by single-cell RNA sequencing in angiotensin (Ang) II-induced AAA mice models. METHOD AND RESULTS: According to 10 × single-cell sequencing analysis, we revealed that ECs inflammation and endothelial-mesenchymal transition (EndoMT) were involved in the progress of Ang II-induced AAA. Three types of ECs, including Mature ECs (uninjured ECs), EndoMT ECs and Injury & inflammation ECs successively emerged during the progression of AAA. By using pseudotime-trajectory analysis, we speculated bone morphogenetic protein 4 (BMP4) as a candidate gene, participating in Ang II-induced AAA by regulating EndoMT and vascular inflammation. We found that inhibition of BMP4 ameliorated EndoMT and vascular inflammation in Ang II-induced AAA in vivo. In addition, we found that exogenous BMP4 directly promoted the phenotypic transition, inflammation, cell migration and invasion of mouse aortic endothelial cells via PI3K/AKT/mTOR pathways in vitro. Finally, Protein-protein interaction (PPI) analysis and co-immunoprecipitation (Co-IP) revealed that biglycan (BGN) directly combined with BMP4 and promoted the conversion of EndoMT. CONCLUSION: Our findings firstly revealed a critical role of BMP4 in AAA progression, which promoted disease progression by inducing EndoMT and reprogramming ECs from anti-inflammatory to proinflammatory phenotype.