Fetal Determinants of Atherosclerosis

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DESCRIPTION (provided by applicant): We previously showed that atherogenesis already begins during fetal development and that maternal hypercholesterolemia during pregnancy is associated with enhanced fatty streak formation in fetuses and a much faster progression of atherosclerosis in normocholesterolemic children that could not be explained by conventional risk factors. Although in humans inherited genetic differences are likely to contribute, we hypothesize that maternal hypercholesterolemia per se induces pathogenic events in fetal arteries that determine their later susceptibility to atherosclerosis. We also hypothesize that oxidative stress caused by maternal hypercholesterolemia leads to persistent changes in the expression of genes modulating atherogenesis. An important corollary is that cholesterol lowering and antioxidant interventions in mothers during pregnancy may provide long-lasting benefits to their offspring. Using genetically homogeneous animal models, we recently provided direct evidence for the causal role of maternal hypercholesterolemia and oxidative stress in both enhanced fetal lesion formation and accelerated post-natal atherogenesis. We also provided proof in principle for persistent regulation of gene expression in the arterial wall. We now propose to better define the in utero programming associated with maternal hypercholesterolemia, to identify genes influencing post-natal susceptibility to atherosclerosis, and to investigate whether interventions during pregnancy also decrease the susceptibility in offspring of "normocholesterolemic" mothers. Different levels of maternal hypercholesterolemia and antioxidant protection will be achieved by transferring embryos of LDL receptor deficient (LDLR-/-) mice into treated or untreated C57BL/6, LDLR -/- or apoE -/- mice. Offspring will be subjected to post-natal atherogenic conditions and lesion formation followed over time. Laser-capture microdissection, gene microarray and PCR techniques will be used to determine persistence of gene regulation and its correlation with atherosclerosis, immunocytochemical presence of gene products and measurements of oxidative stress. These studies should yield fundamentally new insights into in utero programming and atherogenic mechanisms, and may establish a novel preventive approach.