OCT4 has an atheroprotective role in endothelial cells by preventing metabolic and phenotypic dysfunction

Until recently, the pluripotency factor OCT4 was believed to be dispensable in adult somatic cells. However, our recent studies provided clear evidence that OCT4 has a critical atheroprotective role in smooth muscle cells (SMC). Here, we demonstrate that OCT4 controls endothelial cell (EC) phenotypic modulation in atherosclerosis. We establish a new atheroprotective function for OCT4, in that EC-specific Oct4 knockout resulted in increased lipid and LGALS3+ cell accumulation, and altered plaque characteristics consistent with decreased plaque stability. A combination of single-cell RNA sequencing and EC-lineage-tracing studies revealed increased EC activation, endothelial-to-mesenchymal transitions, plaque neovascularization, and mitochondrial dysfunction in the absence of OCT4. We show that ATP transporter, ABCG2, is a direct target of OCT4 in EC, and establish for the first time that the OCT4/ABCG2 axis maintains EC metabolic homeostasis by regulating intracellular heme accumulation and related reactive oxygen species production, which, in turn, contributes to atherogenesis. These results provide the first direct evidence that OCT4 has a protective metabolic function in EC, and identifies vascular OCT4 and its signaling axis as a potential target for novel therapeutics. Overall design: Comparison of wild-type and Oct4 knockout aortic and lung endothelial cells sorted from EC lineage tracing Apoe knockout mice after 5 week of Western diet feeding