Clinical, Metabolic and Molecular Physiology Research Group, University of Nottingham, Nottingham NG7 2RD, UK.
Department of Obstetrics & Gynaecology, University of Nottingham, Nottingham NG7 2RD, UK.
Int J Mol Sci. 2021 Jul 7;22(14):7295. doi: 10.3390/ijms22147295.
Up to 11% of pregnancies extend to post-term with adverse obstetric events linked to pregnancies over 42 weeks. Oxidative stress and senescence (cells stop growing and dividing by irreversibly arresting their cell cycle and gradually ageing) can result in diminished cell function. There are no detailed studies of placental cell senescence markers across a range of gestational ages, although increased levels have been linked to pre-eclampsia before full term. This study aimed to determine placental senescence and oxidative markers across a range of gestational ages in women with uncomplicated pregnancies and those with a diagnosis of pre-eclampsia. Placentae were obtained from 37 women with uncomplicated pregnancies of 37-42 weeks and from 13 cases of pre-eclampsia of 31-41 weeks. The expression of markers of senescence, oxidative stress, and antioxidant defence (tumour suppressor protein p16, kinase inhibitor p21, interleukin-6 (IL-6), NADPH oxidase 4 (NOX4), glutathione peroxidases 1, 3, and 4 (GPx1, GPx3, and GPx4), placental growth factor (PlGF), and soluble fms-like tyrosine kinase-1 (sFlt-1)) genes was measured (quantitative real-time PCR). Protein abundance of p16, IL-6, NOX4, 8-hydroxy-2'-deoxy-guanosine (8-OHdG), and PlGF was assessed by immunocytochemistry. Placental NOX4 protein was higher in post-term than term deliveries and further increased by pre-eclampsia ( < 0.05 for all). P21 expression was higher in post-term placentae ( = 0.012) and in pre-eclampsia ( = 0.04), compared to term. Placental P16 protein expression was increased post-term, compared to term ( = 0.01). In normotensive women, gestational age at delivery was negatively associated with GPx4 and PlGF (mRNA and protein) ( < 0.05 for all), whereas a positive correlation was seen with placental P21, NOX4, and P16 ( < 0.05 for all) expression. Markers of placental oxidative stress and senescence appear to increase as gestational age increases, with antioxidant defences diminishing concomitantly. These observations increase our understanding of placental health and may contribute to assessment of the optimal gestational age for delivery.
高达 11%的妊娠会延长至过期妊娠，与 42 周以上妊娠相关的不良产科事件。氧化应激和衰老（细胞通过不可逆地停止细胞周期并逐渐衰老而停止生长和分裂）可导致细胞功能下降。尽管在足月前与子痫前期有关，但尚未对整个妊娠期胎盘细胞衰老标志物进行详细研究。本研究旨在确定正常妊娠和子痫前期孕妇中各种妊娠龄的胎盘衰老和氧化标志物。从 37 名孕龄 37-42 周的正常妊娠妇女和 13 名孕龄 31-41 周的子痫前期妇女中获得胎盘。检测衰老、氧化应激和抗氧化防御标志物（肿瘤抑制蛋白 p16、激酶抑制剂 p21、白细胞介素-6（IL-6）、NADPH 氧化酶 4（NOX4）、谷胱甘肽过氧化物酶 1、3 和 4（GPx1、GPx3 和 GPx4）、胎盘生长因子（PlGF）和可溶性 fms 样酪氨酸激酶-1（sFlt-1））的基因表达（定量实时 PCR）。通过免疫细胞化学评估 p16、IL-6、NOX4、8-羟基-2'-脱氧鸟苷（8-OHdG）和 PlGF 的蛋白丰度。胎盘 NOX4 蛋白在过期妊娠中高于足月分娩，并进一步增加子痫前期（所有 P < 0.05）。与足月相比，p21 在过期胎盘（=0.012）和子痫前期（=0.04）中表达更高。与足月相比，胎盘 P16 蛋白表达在过期时增加（P=0.01）。在正常血压的女性中，分娩时的孕龄与 GPx4 和 PlGF（mRNA 和蛋白）呈负相关（所有 P < 0.05），而与胎盘 P21、NOX4 和 P16 的表达呈正相关（所有 P < 0.05）。随着妊娠年龄的增加，胎盘氧化应激和衰老的标志物似乎增加，同时抗氧化防御相应减少。这些观察结果增加了我们对胎盘健康的理解，并可能有助于评估最佳分娩孕龄。
