Objective—
Experimental studies suggest that maternal hypercholesterolemia may be relevant for the early onset of cardiovascular disease in offspring. We investigated the effect of perinatal hypercholesterolemia on the atherosclerosis development in the offspring of apolipoprotein E–deficient mice and the underlying mechanism.
Approach and Results—
Atherosclerosis and related parameters were studied in adult male or female apolipoprotein E–deficient mice offspring from either normocholesterolemic or hypercholesterolemic mothers and normocholesterolemic fathers. Female born to hypercholesterolemic mothers had more aortic root lesions than female born to normocholesterolemic mothers. Lesions in whole aorta did not differ between groups. Higher trimethylamine-N-oxide levels and
Fmo3
hepatic gene expression were higher in female born to hypercholesterolemic mothers offspring compared with female born to normocholesterolemic mothers and male. Trimethylamine-N-oxide levels were correlated with the size of atherosclerotic root lesions. Levels of hepatic cholesterol and gallbladder bile acid were greater in male born to hypercholesterolemic mothers compared with male born to normocholesterolemic mothers. At 18 weeks of age, female born to hypercholesterolemic mothers showed lower hepatic
Scarb1
and
Cyp7a1
but higher
Nr1h4
gene expression compared with female born to normocholesterolemic mothers. Male born to hypercholesterolemic mothers showed an increase in
Scarb1
and
Ldlr
gene expression compared with male born to normocholesterolemic mothers. At 25 weeks of age, female born to hypercholesterolemic mothers had lower
Cyp7a1
gene expression compared with female born to normocholesterolemic mothers. DNA methylation of
Fmo3, Scarb1
, and
Ldlr
promoter regions was slightly modified and may explain the mRNA expression modulation.
Conclusions—
Our findings suggest that maternal hypercholesterolemia may exacerbate the development of atherosclerosis in female offspring by affecting metabolism of trimethylamine-N-oxide and bile acids. These data could be explained by epigenetic alterations.
Maternal Hypercholesterolemia During Pregnancy Promotes Early Atherogenesis in LDL Receptor-Deficient Mice and Alters Aortic Gene Expression Determined by Microarray
