CEBPB drives endothelial pathological phenotype and promotes atherosclerosis by directly upregulating TGFBR1 expression [CUT&Tag-Seq]

Endothelial cell (EC) dysfunction is crucial in chronic vascular inflammation and diseases like atherosclerosis. An unknown endothelial pathological phenotype potentially driving atherosclerosis was hinted in our previous study. However, the detailed characterizations and underlying molecular mechanisms remain unclear. In the present study, using single-cell RNA sequencing, the new endothelial pathological phenotype was defined by high expression of fibroblast markers, extracellular matrix, and inflammatory genes, concurrently with a rapid decline in endothelial markers. Further analysis revealed that increased CEBPB contributes to the fibroblast and inflammatory feature of these atherogenic ECs, which was further confirmed in cultured human aortic ECs. Mechanistically, IL-1β-induced high expression of CEBPB triggers TGF-β signaling and subsequent regulation of downstream genes. By performing CUT&Tag analysis, we further investigated that CEBPB directly regulates TGFBR1 expression in endothelial cells through direct interaction of CEBPB with the promotor region of TGF-β receptor type I (TGFBR1). These findings suggest endothelial CEBPB functions as a novel regulator of TGFBR1, driving endothelial pathological phenotype, promoting vascular inflammation and atherosclerosis.