Maternal vitamin D sufficiency and reduced placental gene expression in angiogenic biomarkers related to comorbidities of pregnancy

Abstract

Introduction: Maternal circulating 25-hydroxyvitamin D [25(OH)D] has been shown to optimize production of 1,25-dihydroxyvitamin D [1,25(OH)₂D] during pregnancy at approximately 100nmoles/L, which has pronounced effects on fetal health outcomes. Additionally, associations are noted between low maternal 25(OH)D concentrations and vascular pregnancy complications, such as preeclampsia. To further elucidate the effects of vitamin D activity in pregnancy, we investigated the role of maternal 25(OH)D, the nutritional indicator of vitamin D status, in relation to placental maintenance and, specifically, expression of placental gene targets related to angiogenesis and vitamin D metabolism.

Methods: A focused analysis of placental mRNA expression related to angiogenesis, pregnancy maintenance, and vitamin D metabolism was conducted in placentas from 43 subjects enrolled in a randomized controlled trial supplementing 400IU or 4400IU of vitamin D₃ per day during pregnancy. Placental mRNA was isolated from biopsies within one hour of delivery, followed by quantitative PCR. We classified pregnant women with circulating concentrations of <100nmoles/L as deficient and those with ≥100nmoles/L as sufficient. The value of each gene's change in the PCR cycle threshold (ΔCT), which is a relative measure of target concentration, was compared with maternal 25(OH)D concentrations <100nmoles/L and ≥100nmoles/L based on a two-sample Wilcoxon test.

Results: Soluble FMS-like tyrosine kinase 1 (sFlt-1) and vascular endothelial growth factor (VEGF) gene expression was significantly downregulated in the maternal subgroup with circulating 25(OH)D ≥100ng/mL compared to the subgroup <100ng/mL.

Discussion: Here, we report a significant association between maternal vitamin D status and the expression of sFlt-1 and VEGF at the mRNA level. Achieving maternal circulating 25(OH)D ≥100nmoles/L suggests the impact of maternal vitamin D₃ supplementation on gene transcription in the placenta, thereby potentially decreasing antiangiogenic factors that may contribute to vascular pregnancy complications.

Keywords: Placenta; Preeclampsia; Vascular endothelial growth factor; Vitamin D; sFlt-1.

Figure 2.

Placental target gene expression in vitamin D sufficient cohort as compared to deficient women. Calculated fold change difference between vitamin D deficient vs sufficient groups. Shown negative values indicate downregulation and positive values indicate upregulation in women who were sufficient. Comparatively, vitamin D sufficiency resulted in downregulation of all but three of the genes tested. Results represent the fold change +/− standard deviation of each target gene. Genes with significant results are shown with an asterisk (*).