Abstract
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+2–41+2 weeks. The expression of markers of senescence, oxidative stress, and antioxidant defence (tumour suppressor protein p16INK4a, 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 p16INK4a, 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 (p < 0.05 for all). P21 expression was higher in post-term placentae (p = 0.012) and in pre-eclampsia (p = 0.04), compared to term. Placental P16INK4a protein expression was increased post-term, compared to term (p = 0.01). In normotensive women, gestational age at delivery was negatively associated with GPx4 and PlGF (mRNA and protein) (p < 0.05 for all), whereas a positive correlation was seen with placental P21, NOX4, and P16INK4a (p < 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.
Highlights
The human placenta stops growing at ~90% of full term (~36 weeks of gestation), unlike that of other mammalian species, but the fetus continues to grow, which would presumably “stress” even a normal placenta
We examined the mRNA expression and protein abundance of a panel of markers of cell senescence (P16INK4α, P21, and IL-6), oxidative stress (NADPH oxidase 4 (NOX4), 8-Oxo-20 -deoxyguanosine (8-OHdg), a marker of DNA modification), antioxidant defence (glutathione peroxidases (GPx)), and placental function (PlGF and sFlt-1) in normotensive control and post-term placenta, as well as from women with pre-eclampsia
When further sub-grouped by gestational age, we found significantly higher GPx4 gene expression in the 37–39+0 -week placentae
Summary
The human placenta stops growing at ~90% of full term (~36 weeks of gestation), unlike that of other mammalian species, but the fetus continues to grow, which would presumably “stress” even a normal placenta. This feature is assumed to have evolved in parallel with upright posture and the necessary development of a very muscular uterus, delaying delivery. Ageing is a process that causes a deterioration in function at the cellular, tissue, and organ level, leading to individuals being more susceptible to disease. Telomeres reach a dangerously short length, which initiates the process of cellular senescence, through which cells irreversibly stop growing and dividing by arresting their cell cycle and gradually ageing (becoming ‘senescent’) [2,3]
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