A double-hit pre-eclampsia model results in sex-specific growth restriction patterns
A double-hit pre-eclampsia model results in sex-specific growth restriction patterns
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DOI：
10.1242/dmm.035980
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发表时间：
2019-02-01
影响因子：
4.3
通讯作者：
Plosch, Torsten
中科院分区：
文献类型：
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作者：
Stojanovska, Violeta;Dijkstra, Dorieke J.;Plosch, Torsten
先兆子痫是一种多因素妊娠相关疾病，其特征在于血管生成失衡和全身性炎症;然而，缺乏联合收割机结合这两种病理生理条件的动物模型。在这里，我们介绍了一种新的双重打击先兆子痫小鼠模型，模拟先兆子痫过程中存在的复杂的多因素条件，并允许对胎儿的早期后果的调查。腺病毒过表达可溶性fms样酪氨酸激酶（sFlt-1）和脂多糖（LPS）管理在妊娠中期的小鼠导致高血压和蛋白尿的表现在人类相当。代谢组学分析显示，先兆子痫母鼠的血浆磷酸化胆碱浓度增加。两种性别的胎仔都受到生长限制;然而，在雄性中，脑保护效应被视为对这种生长限制的补偿。根据血浆代谢组学，男性胎儿显示氨基酸代谢的变化，而女性胎儿显示脂质代谢的明显改变。我们的研究结果表明，sFlt-1和LPS的联合暴露模拟了先兆子痫的临床症状，并以性别特异性方式影响胎儿生长，伴随代谢组学变化。
Pre-eclampsia is a multifactorial pregnancy-associated disorder characterized by angiogenic dysbalance and systemic inflammation; however, animal models that combine these two pathophysiological conditions are missing. Here, we introduce a novel double-hit pre-eclampsia mouse model that mimics the complex multifactorial conditions present during pre-eclampsia and allows for the investigation of early consequences for the fetus. Adenoviral overexpression of soluble fms-like tyrosine kinase (sFlt-1) and lipopolysaccharide (LPS) administration at mid-gestation in pregnant mice resulted in hypertension and albuminuria comparable to that of the manifestation in humans. A metabolomics analysis revealed that pre-eclamptic dams have increased plasma concentrations of phosphadytilcholines. The fetuses of both sexes were growth restricted; however, in males a brain-sparing effect was seen as compensation for this growth restriction. According to the plasma metabolomics, male fetuses showed changes in amino acid metabolism, while female fetuses showed pronounced alterations in lipid metabolism. Our results show that combined exposure to sFlt-1 and LPS mimics the clinical symptoms of pre-eclampsia and affects fetal growth in a sex-specific manner, with accompanying metabolome changes.