Fetal Determinants of Atherosclerosis

描述（由申请人提供）：我们先前表明动脉粥样硬化形成在胎儿发育期间已经开始，并且妊娠期间母体高胆固醇血症与胎儿脂肪条纹形成增强以及胆固醇正常儿童动脉粥样硬化进展更快相关，这无法用常规风险因素解释。虽然在人类遗传的遗传差异可能作出贡献，我们假设，母体高胆固醇血症本身诱导的致病事件在胎儿动脉，决定他们以后的动脉粥样硬化的易感性。我们还假设，由母体高胆固醇血症引起的氧化应激导致动脉粥样硬化形成调控基因表达的持续变化。一个重要的推论是，母亲在怀孕期间降低胆固醇和抗氧化干预可能会为其后代提供长期的益处。使用遗传同质的动物模型，我们最近提供了直接的证据，母亲高胆固醇血症和氧化应激的因果关系的作用，在这两个增强胎儿病变的形成和加速出生后动脉粥样硬化。我们还提供了动脉壁基因表达持续调节的原则证据。我们现在建议更好地定义与母体高胆固醇血症相关的子宫内编程，以确定影响出生后动脉粥样硬化易感性的基因，并调查怀孕期间的干预是否也会降低“正常胆固醇血症”母亲后代的易感性。通过将LDL受体缺陷（LDLR-/-）小鼠的胚胎移植到经处理或未经处理的C57 BL/6、LDLR -/-或apoE -/-小鼠中，将实现不同水平的母体高胆固醇血症和抗氧化剂保护。后代将经历出生后致动脉粥样硬化条件，并随时间推移形成病变。激光捕获显微切割，基因微阵列和PCR技术将用于确定基因调控的持久性及其与动脉粥样硬化，基因产物的免疫细胞化学存在和氧化应激的测量的相关性。这些研究应该产生子宫内编程和动脉粥样硬化机制的新见解，并可能建立一种新的预防方法。

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.