Endothelial OCT4 is atheroprotective by preventing metabolic and phenotypic dysfunction.

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Endothelial Cell Biology

Background:

• Octamer-binding transcriptional factor 4 (OCT4) was considered dispensable in adult somatic cells.
• Recent evidence highlights OCT4's atheroprotective role in smooth muscle cells.
• This study investigates OCT4's function in endothelial cells (ECs) within atherosclerosis.

Purpose of the Study:

• To determine the role of OCT4 in regulating EC phenotypic modulations in atherosclerosis.
• To elucidate the molecular mechanisms by which OCT4 influences EC function and atherogenesis.

Main Methods:

• Endothelial cell-specific Oct4 knockout mouse model.
• Single-cell RNA sequencing.
• EC-lineage tracing studies.
• Analysis of plaque characteristics, lipid accumulation, and cell populations.

Main Results:

• EC-specific Oct4 deletion increased lipid and LGALS3+ cell accumulation, decreasing plaque stability.
• Loss of OCT4 led to EC activation, endothelial-to-mesenchymal transition, plaque neovascularization, and mitochondrial dysfunction.
• OCT4 directly targets ABCG2, maintaining EC metabolic homeostasis by regulating heme and reactive oxygen species (ROS) production.

Conclusions:

• OCT4 has a critical protective metabolic function in ECs.
• The OCT4/ABCG2 axis is essential for maintaining EC metabolic homeostasis.
• Targeting vascular OCT4 and its signaling axis offers potential therapeutic strategies for atherosclerosis.