Maternal high-fat diet exacerbates atherosclerosis development in offspring through epigenetic memory.

Maternal exposure to a Western-type diet (WD) increases the susceptibility of adult offspring to atherosclerosis, partly because fetal endothelial cells (ECs) become dysfunctional and inflamed due to risk factors transmitted via maternal-fetal blood exchange. However, the underlying mechanisms remain unclear. Here we show that maternal WD accelerates atherogenesis in adult offspring mice by regulating chromatin dynamics through activator protein-1 (AP-1) in aortic ECs, inducing inflammatory memory at the chromatin level. We found that 27-hydroxycholesterol is involved in memory establishment and also acts as a secondary stimulator, amplifying the expression of inflammatory factors and enhancing the enrichment of AP-1/p300 and H3K27ac in ECs. Inhibiting AP-1 binding to chromatin reduced the inflammatory response in human umbilical vein ECs from mothers with hypercholesterolemia and decreased atherogenesis in offspring mice exposed to maternal WD. Our findings demonstrate that maternal WD exacerbates EC dysfunction and atherosclerosis in adult offspring by inducing AP-1-associated epigenetic memory, which increases chromatin accessibility to inflammatory genes.