Intrauterine exposure to maternal atherosclerotic risk factors increases the susceptibility to atherosclerosis in adult life
Intrauterine exposure to maternal atherosclerotic risk factors increases the susceptibility to atherosclerosis in adult life
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DOI：
10.1161/01.atv.0000282193.31936.fd
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发表时间：
2007-10-01
影响因子：
8.7
通讯作者：
DeRuiter, Marco C.
中科院分区：
文献类型：
--
作者：
Alkemade, Fanneke E.;Gittenberger-de Groot, Adriana C.;DeRuiter, Marco C.
目的：母亲高胆固醇血症与新生儿动脉粥样硬化病变的高发病率和更快进展有关。我们的目的是确定子宫环境是否会使胎儿暴露于母体高胆固醇血症和相关危险因素，从而使小鼠血管壁在成年后加速心血管疾病的发展。方法与结果：为了研究子宫内的表观遗传效应，我们从野生型或载脂蛋白e缺乏背景的母亲中获得遗传相同的杂合载脂蛋白e缺陷后代。载脂蛋白e缺乏母亲的胎儿颈动脉内皮细胞体积损失显著增加，但没有脂肪条纹形成。成年后主动脉和颈动脉没有自发性动脉粥样硬化的发生。我们单侧在颈动脉周围放置一个收缩颈圈来诱导病变的形成。在载脂蛋白e缺陷母鼠的后代中，项圈放置导致10只小鼠中有9只小鼠出现严重的新内膜形成，而野生型母鼠的后代只有较小的病变体积（10只中有2只）。结论：形态学正常的成人动脉对新内膜形成的易感性在产前发育阶段就已经存在，并在成年生活中表现为存在其他动脉粥样硬化危险因素。未来的研究将集中在这一启动过程中涉及的机制以及预防策略上。
Objective-Maternal hypercholesterolemia is associated with a higher incidence and faster progression of atherosclerotic lesions in neonatal offspring. We aimed to determine whether an in utero environment exposing a fetus to maternal hypercholesterolemia and associated risk factors can prime the murine vessel wall to accelerated development of cardiovascular disease in adult life.Methods and Results-To investigate the epigenetic effect in utero, we generated genetically identical heterozygous apolipoprotein E-deficient progeny from mothers with a wild-type or apolipoprotein E-deficient background. A significant increase in loss of endothelial cell volume was observed in the carotid arteries of fetuses of apolipoprotein E-deficient mothers, but fatty streak formation was absent. Spontaneous atherosclerosis development was absent in the aorta and carotid arteries in adult life. We unilaterally placed a constrictive collar around the carotid artery to induce lesion formation. In offspring from apolipoprotein E-deficient mothers, collar placement resulted in severe neointima formation in 9 of 10 mice analyzed compared with only minor lesion volume (2 of 10) in the progeny of wild-type mothers.Conclusions-We conclude that the susceptibility to neointima formation of morphologically normal adult arteries is already imprinted during prenatal development and manifests itself in the presence of additional atherogenic risk factors in adult life. Future research will concentrate on the mechanisms involved in this priming process, as well as on prevention strategies.