背景:先兆子痫的特征是母体内皮激活和胎盘功能障碍。母体血管生成和血管活性因子的失衡与病理生理学有关。胎盘作为这些因素的来源的贡献尚不清楚。此外,对胎儿血管生成和血管活性蛋白以及母体和胎儿水平之间的关系知之甚少。
目的:我们描述胎盘生长因子,可溶性Fms样酪氨酸激酶1,可溶性内皮糖蛋白,和内皮素1-3在健康怀孕的5个血管,早发型和晚发型先兆子痫。具体来说,我们的目的是(1)比较早发和晚发型先兆子痫母胎界面血管中的蛋白质丰度,和健康的怀孕,(2)描述胎盘摄取和蛋白质的释放,和(3)描述母体与胎儿循环中的蛋白质丰度。
方法:从母体桡动脉采集样本,子宫静脉和肘前静脉,75例健康人和37例先兆子痫母胎对(包括19例早发型先兆子痫和18例晚发型先兆子痫)的胎儿脐静脉和动脉,在预定的剖宫产期间。该方法允许通过计算胎盘两侧的静脉动脉差异来估计胎盘释放和蛋白质的摄取。基于微阵列的SomaScan测定定量蛋白质。
结果:子痫前期母体血管中可溶性Fms样酪氨酸激酶1和内皮素1的丰度高于健康妊娠,在早发型先兆子痫中丰度最高。早发型先兆子痫的母体血管中的胎盘生长因子低于健康和晚发型先兆子痫。先兆子痫孕妇内皮素2较高,晚发型先兆子痫的丰度最高。我们的模型证实胎盘生长因子和可溶性Fms样酪氨酸激酶1释放到所有组的母体循环。在健康和晚发型先兆子痫妊娠中,胎盘将可溶性Fms样酪氨酸激酶1释放到胎儿循环中。早发型子痫前期胎儿内皮素1和可溶性Fms样酪氨酸激酶1较高,而两个先兆子痫组的可溶性内皮糖蛋白和内皮素3均低于健康对照组。跨群体,胎盘生长因子的丰度,母体动脉中可溶性Fms样酪氨酸激酶1和内皮素3高于胎儿脐静脉,而内皮素2较低。
结论:在健康人群中,母体可溶性Fms样酪氨酸激酶1和内皮素1的丰度增加,晚发型先兆子痫和早发型联合存在正相关,提示这些蛋白与疾病的病理生理和严重程度相关.早发型先兆子痫胎儿循环中内皮素1升高是一个新发现。先兆子痫中蛋白质丰度改变对胎儿发育和健康的长期影响仍然未知。有必要对这些蛋白质参与病理生理学和作为治疗靶标的进一步研究。
BACKGROUND: Preeclampsia is characterized by maternal endothelial activation and placental dysfunction. Imbalance in maternal angiogenic and vasoactive factors has been linked to the pathophysiology. The contribution of the placenta as a source of these factors remains unclear. Furthermore, little is known about fetal angiogenic and vasoactive proteins and the relation between maternal and fetal levels.
OBJECTIVE: We describe placental growth factor, soluble Fms-like tyrosine kinase 1, soluble endoglin, and endothelin 1-3 in 5 vessels in healthy pregnancies, early- and late-onset preeclampsia. Specifically, we aimed to (1) compare protein abundance in vessels at the maternal-fetal interface between early- and late-onset preeclampsia, and healthy pregnancies, (2) describe placental uptake and release of proteins, and (3) describe protein abundance in the maternal vs fetal circulations.
METHODS: Samples were collected from the maternal radial artery, uterine vein and antecubital vein, and fetal umbilical vein and artery in 75 healthy and 37 preeclamptic mother-fetus pairs (including 19 early-onset preeclampsia and 18 late-onset preeclampsia), during scheduled cesarean delivery. This method allows estimation of placental release and uptake of proteins by calculation of venoarterial differences on each side of the placenta. The microarray-based SomaScan assay quantified the proteins.
RESULTS: The abundance of soluble Fms-like tyrosine kinase 1 and endothelin 1 was higher in the maternal vessels in preeclampsia than in healthy pregnancies, with the highest abundance in early-onset preeclampsia. Placental growth factor was lower in the maternal vessels in early-onset preeclampsia than in both healthy and late-onset preeclampsia. Maternal endothelin 2 was higher in preeclampsia, with late-onset preeclampsia having the highest abundance. Our model confirmed placental release of placental growth factor and soluble Fms-like tyrosine kinase 1 to the maternal circulation in all groups. The placenta released soluble Fms-like tyrosine kinase 1 into the fetal circulation in healthy and late-onset preeclampsia pregnancies. Fetal endothelin 1 and soluble Fms-like tyrosine kinase 1 were higher in early-onset preeclampsia, whereas soluble endoglin and endothelin 3 were lower in both preeclampsia groups than healthy controls. Across groups, abundances of placental growth factor, soluble Fms-like tyrosine kinase 1, and endothelin 3 were higher in the maternal artery than the fetal umbilical vein, whereas endothelin 2 was lower.
CONCLUSIONS: An increasing abundance of maternal soluble Fms-like tyrosine kinase 1 and endothelin 1 across the groups healthy, late-onset preeclampsia and early-onset combined with a positive correlation may suggest that these proteins are associated with the pathophysiology and severity of the disease. Elevated endothelin 1 in the fetal circulation in early-onset preeclampsia represents a novel finding. The long-term effects of altered protein abundance in preeclampsia on fetal development and health remain unknown. Further investigation of these proteins\' involvement in the pathophysiology and as treatment targets is warranted.