The role of nuclear factor kappa B in the pathogenesis of fetal growth restriction depending on vitamin D3 status

Abstract

Fetal growth restriction (FGR) is one of the most severe complications of pregnancy, associated with high perinatal morbidity and adverse long-term outcomes. Placental dysfunction plays a leading role in the pathogenesis of FGR and is accompanied by chronic inflammation and activation of NF‑κB-dependent signaling pathways. Growing evidence suggests that vitamin D₃ deficiency contributes to the development of a proinflammatory placental phenotype.

Aim - to assess the relationship between vitamin D₃ status and p65 NF‑κB activity in the placenta of pregnant women with fetal growth restriction.

Materials and methods. A total of 110 pregnant women were enrolled in the study: Group I (n=45) - FGR combined with vitamin D₃ deficiency (≤20 ng/mL); Group II (n=35) - FGR with an optimal vitamin D₃ level (>30 ng/mL). The control group (n=30) included women with physiologic pregnancies and optimal vitamin D₃ levels. Serum 25(OH)D concentrations were measured using enzyme-linked immunosorbent assay (ELISA). p65 NF‑κB activity in placental lysates was assessed by determining the ratio of phosphorylated to total p65 NF‑κB using ELISA. Statistical analysis was performed using parametric and nonparametric tests; was considered statistically significant.

Results. Women with FGR and vitamin D₃ deficiency demonstrated the highest levels of NF‑κB activation: total p65 NF‑κB - 62.2 (60.7-64.2) pg/mL; phosphorylated p65 NF‑κB - 28.8 (24.8-32.1) pg/mL; p65 NF‑κB activity - 55.8 (54.1-57.2)%, which were significantly higher than those observed in the control group. In patients with FGR and optimal vitamin D₃ levels, NF‑κB activation markers were significantly lower than in women with vitamin D₃ deficiency (p<0.05), but remained higher than in controls.

Conclusions. Fetal growth restriction is associated with pronounced activation of NF‑κB-dependent proinflammatory signaling pathways in the placenta. Vitamin D₃ deficiency markedly enhances p65 NF‑κB activation, promoting the development of a proinflammatory placental dysfunction phenotype. An optimal vitamin D₃ level exerts a partial protective effect by limiting the intensity of the inflammatory response. The vitamin D₃/VDR ↔ NF‑κB p65 axis may represent a promising pathogenetic target for the prevention and reduction of FGR severity.

The study was performed in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by the Bioethics and Deontology Committee of the institution mentioned in the work. Informed consent of the patients was obtained for the research.

The authors declare no conflict of interest.