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Maternal Fibroblast Growth Factor 21 Levels Decrease during Early Pregnancy in Normotensive Pregnant Women but Are Higher in Preeclamptic Women—A Longitudinal Study

ABSTRACT: (1) Background: Fibroblast growth factor 21 (FGF-21) is an endocrine factor involved in glucose and lipid metabolism that exerts pleiotropic effects. The aim of this study was to investigate the serum FGF-21 profile in healthy and mild preeclamptic pregnant women at each trimester of pregnancy; (2) Methods: Serum FGF-21 levels were determined by ELISA in a nested case-control study within a longitudinal cohort study that included healthy (n = 54) and mild preeclamptic (n = 20) pregnant women, women at three months after delivery (n = 20) and eumenorrheic women during the menstrual cycle (n = 20); (3) Results: FGF-21 levels were significantly lower in the mid-luteal phase compared to the early follicular phase of the menstrual cycle in eumenorrheic women (p < 0.01). Maternal levels of FGF-21 were significantly lower in the first and second trimesters and peaked during the third trimester in healthy pregnant women (p < 0.01). Serum levels of FGF-21 in healthy pregnant were significantly lower in the first and second trimester of pregnancy compared with the follicular phase of the menstrual cycle and postpartum (p < 0.01). Serum FGF-21 levels were significantly higher in preeclamptic compared to healthy pregnant women during pregnancy (p < 0.01); (4) Conclusions: These results suggest that a peak of FGF-21 towards the end of pregnancy in healthy pregnancy and higher levels in preeclamptic women might play a critical role that contributes to protecting against the negatives effects of high concentrations of non-esterified fatty acids (NEFA) and hypertensive disorder. Furthermore, FGF-21 might play an important role in reproductive function in healthy eumenorrheic women during the menstrual cycle.

SUBMITTER: Buell-Acosta J

PROVIDER: S-EPMC9322099 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Preeclampsia (PE), as a multisystem disorder, is associated with maternal hypertension and proteinuria. Apoptosis seems to be involved in the pathophysiology of PE, although its precise pathogenic mechanisms are not well established. In this study, we aimed to identify the association between maternal TP53-rs1042522, P21-rs1801270, and P21-rs1059234 polymorphisms and PE. In addition, we examined the effects of promoter methylation and TP53 and P21 polymorphisms on placental mRNA expression in PE women. METHODS:The blood of 226 PE women and 228 normotensive pregnant women was examined in this study. In addition, the placentas were genotyped in 109 PE and 112 control women. The methylation status was assessed by a methylation-specific PCR assay, while mRNA expression was examined via Quantitative Real Time PCR. RESULTS:The maternal and placental P21-rs1801270 CA genotype had a significant association with the reduced risk of PE. In the dominant, recessive, and allelic models, maternal/placental P21-rs1059234 polymorphism had no statistically significant association with the risk of PE. On the other hand, the reduced risk of PE was associated with maternal, but not placental TP53-rs1042522 polymorphism in the dominant and recessive models. The maternal and placental P21-rs1801270 polymorphism was associated with PE risk. The maternal P21 Trs1059234Crs1801270 haplotype was associated with 3.4-fold increase in PE risk, However the maternal P21 Trs1059234Ars 1801270 haplotype and placental Crs1059234CA rs1801270 haplotype led to 0.5 and 0.4-fold decrease in PE risk, respectively. PE women showed 5.6 times higher levels of placental mRNA expression of TP53 gene, although it was not associated with rs1042522 polymorphism. The relative placental mRNA expression of P21 gene was 0.2 in PE women. It was also 2.4 times higher in individuals with rs1801270CA genotype than those with AA genotype. The hyper-methylation of P21 and TP53 genes in the promoter region was associated with a 3.4-fold and 3-fold increase in PE risk, respectively. However, no association was found between P21 and TP53 mRNA expression and promoter methylation. CONCLUSION:In conclusion, P21-rs1801270 and TP53-rs1042522 polymorphisms were involved in reduced risk of PE. P21-rs1801270 was associated with decreased P21 mRNA expression. The hyper-methylation of P21 and TP53 genes in the promoter region was associated with a higher PE risk.

Project description:Pregnant women who develop preeclampsia exhibit higher circulating levels of the soluble VEGF receptor-1 (sFlt-1). Recent findings suggest that soluble Flt-1 may contribute to the pathogenesis of preeclampsia by binding and neutralizing vascular endothelial growth factors (VEGF) and placental growth factor (PlGF). Existing literature identifies sFlt-1 as a 100 kDa glycoprotein, a product of an mRNA splice variant. We hypothesized that sFlt-1 expression may be more complex with multiple variants of sFlt-1 as well as multiple sources during normal pregnancy and preeclampsia. Using a combination of affinity purification of sFlt-1 by heparin-agarose and epitope specific antibodies, we performed Western blot analysis with epitope specific antibodies for sFlt-1. Plasma of preeclamptic women exhibits significantly higher amounts of a novel 145 kDa variant of sFlt-1, along with the 100 kDa isoform. We identified sFlt-1 variants in the conditioned medium from placental explant cultures that are hypoxia responsive with varying sizes, including 185, 145,100 and 60 kDa forms, as well as antigenicity. The 145 kDa was similar in antigenicity to the 100 kDa found in plasma whereas the 185 and 60 kDa sFlt-1 demonstrated different epitopes. Deglycosylation studies also confirm that there are multiple sFlt-1 polypeptides. Co-immunoprecipitation with VEGF suggests that these different sFlt isoforms can bind VEGF and therefore, may be of functional importance. Finally, comparison of sFlt-1 in the conditioned medium obtained from cultured cytotrophoblasts, peripheral blood mononuclear cells (PBMCs) and human uterine microvascular cells (HUtMVECs) exhibit mainly the100 kDa sFlt-1. Collectively these data suggest the presence of multiple isoforms of sFlt-1 in the circulation of women with preeclampsia as well as in uncomplicated pregnancies and the possibility of multiple sources. Placental hypoxia may contribute to sFlt-1 over expression but other regulatory mechanisms cannot be ruled out.

Project description:BackgroundWhile preeclampsia (PE) is a leading cause of pregnancy-related morbidity/mortality, its underlying mechanisms are not fully understood. DNA methylation (DNAm) is a dynamic regulator of gene expression that may offer insight into PE pathophysiology and/or serve as a biomarker (e.g., risk, subtype, a therapeutic response). This study's purpose was to evaluate for differences in blood-based DNAm across all trimesters between individuals eventually diagnosed with PE (cases) and individuals who remained normotensive throughout pregnancy, did not develop proteinuria, and birthed a normally grown infant (controls).ResultsIn the discovery phase, longitudinal, genome-wide DNAm data were generated across three trimesters of pregnancy in 56 participants (n=28 cases, n=28 controls) individually matched on self-identified race, pre-pregnancy body mass index, smoking, and gestational age at sample collection. An epigenome-wide association study (EWAS) was conducted, using surrogate variable analysis to account for unwanted sources of variation. No CpGs met the genome-wide significance p value threshold of 9×10-8, but 16 CpGs (trimester 1: 5; trimester 2: 1; trimester 3: 10) met the suggestive significance threshold of 1×10-5. DNAm data were also evaluated for differentially methylated regions (DMRs) by PE status. Three DMRs in each trimester were significant after Bonferonni-adjustment. Since only third-trimester samples were available from an independent replication sample (n=64 cases, n=50 controls), the top suggestive hits from trimester 3 (cg16155413 and cg21882990 associated with TRAF3IP2-AS1/TRAF3IP2 genes, which also made up the top DMR) were carried forward for replication. During replication, DNAm data were also generated for validation purposes from discovery phase third trimester samples. While significant associations between DNAm and PE status were observed at both sites in the validation sample, no associations between DNAm and PE status were observed in the independent replication sample.ConclusionsThe discovery phase findings for cg16155413/cg21882990 (TRAF3IP2-AS1/TRAF3IP2) were validated with a new platform but were not replicated in an independent sample. Given the differences in participant characteristics between the discovery and replication samples, we cannot rule out important signals for these CpGs. Additional research is warranted for cg16155413/cg21882990, as well as top hits in trimesters 1-2 and significant DMRs that were not examined in the replication phase.

Project description:ObjectiveAngiopoietin-like protein 3(ANGPTL3) is an important regulator of lipoprotein metabolism in the fed state by inhibiting the enzyme lipoprotein lipase in oxidative tissues. However, the possible role of ANGPTL3 throughout gestation and its relationship with hormonal and biochemical variables are still unknown. The aim of this study was to determinate serum ANGPTL3 level in healthy non-pregnant women, during healthy and preeclamptic pregnancy and postpartum.MethodsSerum ANGPTL3 was analyzed by enzyme-linked immunosorbent assay (ELISA), in a prospective cohort of healthy pregnant women (n = 52) and women with mild preeclampsia (n = 21), and women at three months postpartum (n = 20) and healthy non-pregnant women (n = 20). The results obtained were correlated with biochemical, hormonal and anthropometric variables and insulin resistance indices.ResultsLevels of ANGPTL3 were not different between the follicular and the luteal phases of the cycle in healthy non-pregnant women. There was a significant reduction in serum ANGPTL3 levels from the first to the third trimester in healthy pregnant women compared with healthy non-pregnant and postpartum women (p <0.01). ANGPTL3 levels do not differ significantly during the three trimesters of pregnancy neither in healthy women nor in preeclamptic women. The serum levels of ANGPTL3 in women who developed preeclampsia are not statistically different from those observed in healthy pregnant women in each trimester of pregnancy. A significant lineal positive correlation was observed between serum ANGPTL3 levels and triglyceride (P =0.0186, r =0.52), very low-density lipoprotein cholesterol (P =0.0224, r =0.50), and total cholesterol levels (P =0.0220, r =0.50) in healthy non-pregnant women (P 0.05). Besides, there were no significant correlations between serum ANGPTL3 and body mass index (BMI), high-density lipoprotein cholesterol, glucose, insulin, leptin, or HOMA-IR (P >0.05).ConclusionsWe describe for the first time the profile of ANGPTL3 throughout pregnancy and postpartum as well as and discussed about explore their potential contribution interactions with lipoprotein metabolism throughout pregnancy and postpartum. Thus, low levels of ANGPTL3 during pregnancy might favor lipid uptake in oxidative tissues as the main maternal energy source, while may helping to preserve glucose for use by the fetus and placenta.

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Maternal Fibroblast Growth Factor 21 Levels Decrease during Early Pregnancy in Normotensive Pregnant Women but Are Higher in Preeclamptic Women—A Longitudinal Study

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