Maternal high-fat diet aggravates the development of atherosclerosis in offspring via epigenetic memory (ATAC-Seq CUT&Tag)

Maternal exposure to a western-type diet (WD) increases the susceptibility of adult offspring to atherosclerosis. Lining the inner layer of blood vessels, fetus endothelial cells (ECs) become dysfunctional and inflamed in response to risk factors from mother through maternal and fetal blood exchange. However, the mechanism by which maternal WD promotes vascular endothelial dysfunction and atherosclerosis in offspring after adulthood has not been fully clarified. Here, we found that maternal WD exposure sensitized offspring to WD exposure in adulthood of Ldlr-/- mice, significantly increasing atherosclerotic lesions in the aorta and aortic roots, endowed inflammatory memory at the chromatin level and regulated chromatin dynamics by transcription factor AP-1 in mouse aortic ECs. Plasma 27-hydroxycholesterol (27-HC) was significantly increased in maternal blood and transferred into the offspring. Additionally, 27-HC played a crucial role in memory establishment and also acted as a secondary stimulator, amplifying the expression of inflammatory memory factors and enhancing the enrichment of AP-1/p300 and H3K27ac in the binding domain in human ECs. Inhibiting AP-1 binding to chromatin reduced the inflammatory response in human umbilical vein ECs from mother with maternal hypercholesterolemia and the occurrence and development of atherosclerosis in the offspring with maternal WD exposure. Our findings demonstrate that maternal WD aggravating EC dysfunction and atherosclerosis in offspring after adulthood acquires AP-1-associated epigenetic memory to increase chromatin accessibility of inflammatory genes. Overall design: We isolated and performed SMART-seq, ATAC-seq, and H3K27ac ChIP-seq on mouse aortic ECs (MAECs) from mice in the CDM-CDO / WDM-CDO groups and in the CDM-WDO / WDM-WDO groups that were given WD again for 4 weeks