Genome-wide expression profiling of placentas in the p57Kip2 model of pre-eclampsia
Genome-wide expression profiling of placentas in the p57Kip2 model of pre-eclampsia
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DOI：
10.1093/molehr/gal116
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发表时间：
2007-04-01
影响因子：
4
通讯作者：
Baker, J. C.
中科院分区：
文献类型：
--
作者：
Knox, K. S.;Baker, J. C.
先兆子痫影响 6-10% 的妊娠，是早产的主要原因之一。人们普遍认为，胎盘发育不当与环境因素相结合，在疾病发病机制中发挥着重要作用。 p57(Kip2) 小鼠是唯一能够重现人类疾病全部症状的先兆子痫小鼠模型，包括胎盘异常、高血压、蛋白尿和早产。此外，表达野生型p57(Kip2)水平的怀孕女性在怀有缺乏p57(Kip2)表达的胎儿时会出现先兆子痫。这表明胎儿或胎盘导致了这种疾病。在这里，利用 p57(Kip2) 小鼠独特的遗传学，我们使用全基因组表达谱在分子水平上定义 p57(Kip2) 表型的胎盘方面，并对涉及先兆子痫发病机制的因素进行公正的搜索。在分析过程中，我们发现虽然突变胚胎表现出胎盘结构改变，并且组织学变化表明子宫胎盘血流量减少，但p57（Kip2）怀孕女性并未表现出高血压或肾脏病理学。这表明胎盘异常仅在考虑到其他环境变量的情况下才会导致先兆子痫。在此模型的基础上，我们预计分子因素的错误调节虽然不能在这种情况下引起全谱的疾病症状，但仍然会发生在这些 p57(Kip2) 突变小鼠中。我们的研究表明环境因素在 p57(Kip2) 先兆子痫表型中发挥作用，并在该模型中确定了几种先兆子痫易感因素，包括已知的血压、炎症和细胞凋亡调节因子。
Pre-eclampsia affects 6-10% of pregnancies and is one of the primary causes of premature birth. It is widely accepted that inappropriate placental development, combined with environmental factors, plays a major role in disease pathogenesis. The p57(Kip2) mouse is the only mouse model of pre-eclampsia that recapitulates the full spectrum of symptoms of the human disease, including placental abnormalities, hypertension, proteinuria and premature labour. In addition, pregnant females expressing wild-type levels of p57(Kip2) develop pre-eclampsia when carrying fetuses that lack p57(Kip2) expression. This demonstrates that either the fetus or the placenta causes the disease. Here, taking advantage of the unique genetics of the p57(Kip2) mouse, we have used full genome expression profiling to define the placental aspect of the p57(Kip2) phenotype at a molecular level and to conduct an unbiased search for factors involved in pre-eclampsia pathogenesis. During this analysis, we found that although mutant embryos demonstrate altered placental architecture and have histological changes indicative of reduced utero-placental blood flow, the p57(Kip2) pregnant females do not demonstrate hypertension or renal pathology. This suggests a model in which placental abnormalities cause pre-eclampsia only given other environmental variables. On the basis of this model, we expect that misregulation of molecular factors, while not able to cause a full spectrum of disease symptoms in this context, still occurs in these p57(Kip2) mutant mice. Our studies suggest a role for environmental factors in the p57(Kip2) pre-eclampsia phenotype and have identified several candidates for pre-eclampsia predisposition in this model, including known regulators of blood pressure, inflammation and apoptosis.