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Advanced maternal age causes premature placental senescence and malformation via dysregulated α-Klotho expression in trophoblasts.

ABSTRACT: Advanced maternal age (AMA) pregnancy is associated with higher risks of adverse perinatal outcomes, which may result from premature senescence of the placenta. α-Klotho is a well-known antiaging protein; however, its expression and effect on the placenta in AMA pregnancies have not yet been fully elucidated. The expression patterns of α-Klotho in mouse and human placentas from AMA pregnancies were determined by Western blotting and immunohistochemistry (IHC) staining. α-Klotho expression in JAR cells was manipulated to investigate its role in trophoblastic senescence, and transwell assays were performed to assess trophoblast invasion. The downstream genes regulated by α-Klotho in JAR cells were first screened by mRNA sequencing in α-Klotho-knockdown and control JAR cells and then validated. α-Klotho-deficient mice were generated by injecting klotho-interfering adenovirus (Ad-Klotho) via the tail vein on GD8.5. Ablation of α-Klotho resulted in not only a senescent phenotype and loss of invasiveness in JAR cells but also a reduction in the transcription of cell adhesion molecule (CAM) genes. Overexpression of α-Klotho significantly improved invasion but did not alter the expression of senescence biomarkers. α-Klotho-deficient mice exhibited placental malformation and, consequently, lower placental and fetal weights. In conclusion, AMA results in reduced α-Klotho expression in placental trophoblasts, therefore leading to premature senescence and loss of invasion (possibly through the downregulation of CAMs), both of which ultimately result in placental malformation and adverse perinatal outcomes.

SUBMITTER: Chen Z

PROVIDER: S-EPMC8282245 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:INTRODUCTION: Antenatal maternal psychological distress may be associated with reduced placental circulation, which could lead to lower birthweight. Studies investigating this in humans show mixed results, which may be partially due to type, strength and timing of distress. In addition, the arterial vascular resistance measures often used as outcome measures do not detect smaller changes in placental volume blood flow. We aimed to investigate the effect of a specific stressor, with increased levels of stress early in pregnancy, on the fetoplacental volume blood flow in third trimester. METHODS: This was a prospective observational study of 74 pregnant women with a congenital malformation in a previous fetus or child. Psychological distress was assessed twice, around 16 and 30 weeks' gestation. Psychometric measures were the General Health Questionnaire-28 (subscales anxiety and depression), Edinburgh Postnatal Depression Scale, and Impact of Event Scale-22 (subscales intrusion, avoidance, and arousal). Placental circulation was examined at 30 weeks, using Doppler ultrasonography, primarily as fetoplacental volume blood flow in the umbilical vein, normalized for abdominal circumference; secondarily as vascular resistance measures, obtained from the umbilical and the uterine arteries. RESULTS: Maternal distress in second but not third trimester was associated with increased normalized fetoplacental blood flow (P-values 0.006 and 0.013 for score > mean for depression and intrusion, respectively). Post-hoc explorations suggested that a reduced birthweight/placental weight ratio may mediate this association. Psychological distress did not affect vascular resistance measures in the umbilical and uterine arteries, regardless of adjustment for confounders. CONCLUSIONS: In pregnant women with a previous fetus or child with a congenital malformation, higher distress levels in second trimester were associated with third trimester fetoplacental blood flow that was higher than expected for the size of the fetus. The results do not support placental blood flow reduction as a pathway between maternal distress and reduced birthweight.

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Advanced maternal age causes premature placental senescence and malformation via dysregulated α-Klotho expression in trophoblasts.

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