Department of Gynaecology and Obstetrics, University Hospital Essen, 45147 Essen, Germany.
Department of Paediatrics I, Neonatology & Experimental Perinatal Neurosciences, University Hospital Essen, 45147 Essen, Germany.
Oxid Med Cell Longev. 2022 Jun 2;2022:3024032. doi: 10.1155/2022/3024032. eCollection 2022.
The pregnancy disorder preeclampsia (PE) is characterized by maternal hypertension, increased level of circulating antiangiogenic soluble fms-like tyrosine kinase-1 (sFLT1), and reduced placental perfusion, leading to foetal growth restriction (FGR) and preterm birth. All these adverse effects are associated with neurocognitive disorders in the offspring. However, the direct interplay between increased antiangiogenesis during PE and disturbed foetal brain development independent of prematurity has not been investigated yet. To examine foetal brain development in sFLT1-related PE, hsFLT1/rtTA-transgenic mice with systemic (maternal or maternal/fetoplacental) human sFLT1 (hsFLT1) overexpression since 10.5 days postconception (dpc) were used, and histological and molecular analyses of foetal brains were performed at 18.5 dpc. Consequences of elevated hsFLT1 on placental/foetal vascularization and hypoxia of placentas and foetal brains were analysed using the hypoxia markers pimonidazole and hemeoxygenase-1 (HO-1). Immunohistochemical analysis revealed increased hypoxia in placentas of PE-affected pregnancies. Moreover, an increase in HO-1 expression was observed upon elevated hsFLT1 in placentas and foetal brains. PE foetuses revealed asymmetrical FGR by increased brain/liver weight ratio. The brain volume was reduced combined with a reduction in the cortical/hippocampal area and an increase of the caudate putamen and its neuroepithelium, which was associated with a reduced cell density in the cortex and increased cell density in the caudate putamen upon hsFLT1 overexpression. Mild influences were observed on brain vasculature shown by free iron deposits and mRNA changes in Vegf signalling. Of note, both types of systemic hsFLT1 overexpression (indirect: maternal or direct: maternal/fetoplacental) revealed similar changes with increasing severity of impaired foetal brain development. Overall, circulating hsFLT1 in PE pregnancies impaired uteroplacental perfusion leading to disturbed foetal oxygenation and brain injury. This might be associated with a disturbed cell migration from the caudate putamen neuroepithelium to the cortex which could be due to disturbed cerebrovascular adaption.
妊娠疾病子痫前期（PE）的特征是母体高血压、循环中血管生成抑制因子可溶性 fms 样酪氨酸激酶-1（sFLT1）水平升高，以及胎盘灌注减少，导致胎儿生长受限（FGR）和早产。所有这些不良后果都与后代的神经认知障碍有关。然而，PE 期间血管生成增加与早产无关的胎儿大脑发育紊乱之间的直接相互作用尚未得到研究。为了研究与 sFLT1 相关的 PE 中的胎儿大脑发育，使用了自妊娠 10.5 天（dpc）以来全身性（母体或母体/胎盘中）过表达人 sFLT1（hsFLT1）的 hsFLT1/rtTA 转基因小鼠，并在 18.5 dpc 时对胎儿大脑进行组织学和分子分析。使用缺氧标志物 pimonidazole 和血红素加氧酶-1（HO-1）分析升高的 hsFLT1 对胎盘/胎儿血管生成和胎盘及胎儿大脑缺氧的影响。免疫组织化学分析显示，PE 影响的妊娠胎盘缺氧增加。此外，在胎盘和胎儿大脑中升高的 hsFLT1 观察到 HO-1 表达增加。PE 胎儿通过增加脑/肝重量比表现出不对称的 FGR。大脑体积减少，皮质/海马区减少，尾状核和其神经上皮增加，这与皮质细胞密度减少和 hsFLT1 过表达时尾状核细胞密度增加有关。在脑血管系统中观察到轻微的影响，表现为游离铁沉积和 Vegf 信号转导中 mRNA 的变化。值得注意的是，两种类型的全身性 hsFLT1 过表达（间接：母体或直接：母体/胎盘中）都显示出相似的变化，随着胎儿大脑发育受损程度的增加而加重。总的来说，PE 妊娠中的循环 hsFLT1 损害了子宫胎盘灌注，导致胎儿缺氧和脑损伤。这可能与从尾状核神经上皮到皮质的细胞迁移紊乱有关，这可能是由于脑血管适应紊乱所致。
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