Department of Obstetrics and Gynaecology, Cork University Maternity Hospital, University College Cork, T12 YE02 Cork, Ireland.
INFANT Research Centre, University College Cork, T12 K8AF Cork, Ireland.
Int J Mol Sci. 2023 Feb 4;24(4):3101. doi: 10.3390/ijms24043101.
Premature ageing of the placenta in pregnancy outcomes is associated with the persistent presence of oxidative stress and placental insufficiency reducing its functional capacity. In this study, we investigated cellular senescence phenotypes of pre-eclampsia and IUGR pregnancies by simultaneously measuring several biomarkers of senescence. Maternal plasma and placental samples were collected at term gestation from nulliparous women undergoing pre-labour elective caesarean section with pre-eclampsia without intrauterine growth restriction (PE; = 5), pre-eclampsia associated with intrauterine growth restriction (n = 8), intrauterine growth restriction (IUGR < 10th centile; = 6), and age-matched controls ( = 20). Placental absolute telomere length and senescence gene analysis was performed by RTqPCR. The expression of cyclin-dependent kinase inhibitors (p21 and p16) was determined by Western blot. Senescence-associated secretory phenotypes (SASPs) were evaluated in maternal plasma by multiplex ELISA assay. Placental expression of senescence-associated genes showed significant increases in CHEK1, PCNA, PTEN, CDKN2A, and CCNB-1 ( < 0.05) in pre-eclampsia, while TBX-2, PCNA, ATM, and CCNB-1 expression were evident ( < 0.05) and were significantly decreased in IUGR compared with controls. Placental p16 protein expression was significantly decreased in pre-eclampsia only compared with controls ( = 0.028). IL-6 was significantly increased in pre-eclampsia (0.54 pg/mL ± 0.271 vs. 0.3 pg/mL ± 0.102; = 0.017) while IFN-γ was significantly increased in IUGR (4.6 pg/mL ± 2.2 vs. 2.17 pg/mL ± 0.8; = 0.002) compared with controls. These results provide evidence of premature senescence in IUGR pregnancies, and while cell cycle checkpoint regulators are activated in pre-eclampsia, the cellular phenotype is one of cell repair and subsequent proliferation rather than progression to senescence. The heterogeneity of these cellular phenotypes highlights the complexity of characterising cellular senescence and may equally be indicative of the differing pathophysiological insults unique to each obstetric complication.
胎盘在妊娠结局中的过早老化与持续存在的氧化应激和胎盘功能不全有关，这会降低其功能能力。在这项研究中，我们通过同时测量几种衰老标志物来研究子痫前期和 IUGR 妊娠的细胞衰老表型。从行择期剖宫产的初产妇中收集足月孕妇的母体血浆和胎盘样本，这些产妇患有无宫内生长受限的子痫前期（PE；n=5）、伴有宫内生长受限的子痫前期（n=8）、宫内生长受限（IUGR < 第 10 百分位数；n=6）和年龄匹配的对照组（n=20）。通过 RTqPCR 进行胎盘绝对端粒长度和衰老基因分析。通过 Western blot 测定细胞周期蛋白依赖性激酶抑制剂（p21 和 p16）的表达。通过多重 ELISA 测定母血浆中的衰老相关分泌表型（SASPs）。胎盘衰老相关基因的表达在子痫前期中显著增加 CHEK1、PCNA、PTEN、CDKN2A 和 CCNB-1（<0.05），而 TBX-2、PCNA、ATM 和 CCNB-1 的表达明显增加（<0.05）且与对照组相比，IUGR 明显降低。与对照组相比，仅子痫前期中胎盘 p16 蛋白表达显著降低（=0.028）。与对照组相比，子痫前期中 IL-6 显著增加（0.54pg/mL±0.271 vs.0.3pg/mL±0.102；=0.017），而 IUGR 中 IFN-γ 显著增加（4.6pg/mL±2.2 vs.2.17pg/mL±0.8；=0.002）。这些结果提供了 IUGR 妊娠中过早衰老的证据，虽然细胞周期检查点调节剂在子痫前期中被激活，但细胞表型是细胞修复和随后增殖的表型，而不是进展为衰老的表型。这些细胞表型的异质性突出了表征细胞衰老的复杂性，并且同样可能表明每种产科并发症特有的不同病理生理损伤。
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