Abstract 1330: Maternal Hypercholesterolemia Accelerates Atherosclerosis Development in Adult Heterozygous Apolipoprotein E Offspring
Maternal hypercholesterolemia has been associated with increased fatty streak formation in fetal aortas. In the neonate, these fatty streaks regress. We hypothesized that intrauterine exposure to maternal hypercholesterolemia leads to accelerated development of atherosclerosis in adult life. To study the effect of maternal hypercholesterolemia, Apoe+/− fetuses (n=120) and adult offspring (n=20) of both Apoe−/− and wild type C57BL/6J mothers were generated. Maternal and fetal plasma cholesterol levels were monitored during pregnancy and in adult life. In adult female Apoe+/− offspring on a high fat diet, a constrictive collar was placed around the left common carotid artery at 16 weeks to induce neointima formation. At embryonic day 17.5 and in offspring, plasma cholesterol levels in Apoe+/− mice were not influenced by maternal hypercholesterolemia. Four weeks after collar placement severe neointima formation was detected in Apoe+/− mice of hypercholesterolemic mothers (9/10) compared with minor lesions in the non-exposed group (2/9). Significant differences were observed in lesion volume (5.04±1.65x106 vs. 0.28±0.18x106 μm3; p=0.018) and intima/media ratio (0.15±0.05 vs. 0.01±0.01; p=0.017). All lesions contained macrophages and foam cells, extensive elastin and collagen deposition, and activated endothelial cells. Immunohistochemistry as well as Affymetrix Microarray analysis of the contralateral untreated carotid arteries from fetally exposed and non-exposed mice revealed no significant differences, indicating that lowered shear stress is required for intimal proliferation. In conclusion, adult arteries that have been exposed to maternal hypercholesterolemia during embryonic development are highly sensitive for development of atherosclerotic plaques. We suggest that maternal hypercholesterolemia through oxidative stress may epigenetically influence monocytes and endothelial cells resulting in an elevated activation response after induced lowered shear stress.