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. 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. 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. 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. 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.

中文翻译：

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健康妊娠和先兆子痫中母胎界面的血管生成和血管活性蛋白

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不平衡与病理生理学有关。胎盘作为这些因素的来源的贡献仍不清楚。此外，对于胎儿血管生成蛋白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。我们描述了健康妊娠、早发型和晚发型子痫前期的 5 条血管中的胎盘生长因子、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。具体来说，我们的目的是（1）比较早发性子痫前期和晚发性先兆子痫与健康妊娠之间母胎界面血管中的蛋白质丰度，（2）描述胎盘摄取和释放蛋白质，以及（3）描述蛋白质丰度在母体循环和胎儿循环中。在预定剖宫产期间从母体桡动脉、子宫静脉和肘前静脉以及胎儿脐静脉和动脉采集了75对健康的和37对先兆子痫的母胎（其中19对是早发性子痫前期，18对是晚发性子痫前期）。 。该方法可以通过计算胎盘两侧的静脉动脉差异来估计胎盘的蛋白质释放和摄取。基于微阵列的 SomaScan 测定对蛋白质进行了定量。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，其中早发子痫前期丰度最高。早发性子痫前期母体血管中的胎盘生长因子低于健康和晚发性子痫前期。先兆子痫患者的母体内皮素 2 较高，其中晚发性先兆子痫的丰度最高。我们的模型证实了所有组中胎盘均向母体循环释放胎盘生长因子和可溶性 Fms 样酪氨酸激酶 1。在健康和晚发性先兆子痫妊娠中，胎盘将可溶性 Fms 样酪氨酸激酶 1 释放到胎儿循环中。早发性先兆子痫组的胎儿内皮素 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。在各组中，母体动脉中胎盘生长因子、可溶性 Fms 样酪氨酸激酶 1 和内皮素 3 的丰度高于胎儿脐静脉，而内皮素 2 的丰度较低。在健康组、晚发性先兆子痫组和早发性先兆子痫组中，母体可溶性 Fms 样酪氨酸激酶 1 和内皮素 1 的丰度不断增加，且呈正相关，这可能表明这些蛋白质与疾病的病理生理学和严重程度相关。早发性先兆子痫胎儿循环中内皮素 1 升高是一项新发现。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不清楚。有必要进一步研究这些蛋白质在病理生理学中的参与以及作为治疗靶点。