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Inflammation-induced fetal growth restriction in rats is associated with increased placental HIF-1? accumulation.

ABSTRACT:

Introduction

Hypoxia-inducible factor 1-alpha (HIF-1?) is the oxygen-sensitive subunit of the transcription factor HIF-1, and its expression is increased in placentas from pregnancies complicated by pre-eclampsia (PE). Fetal growth restriction (FGR) and PE often share a common pathophysiology; however, it is unknown whether increased placental HIF-1? occurs in FGR. We previously demonstrated that aberrant maternal inflammation in rats resulted in altered utero-placental perfusion and FGR, both of which were prevented by administration of the nitric oxide mimetic glyceryl trinitrate (GTN). Our aim here was to determine whether abnormal maternal inflammation causing FGR is linked to placental HIF-1? accumulation and whether GTN administration could prevent increases in placental HIF-1?.

Methods

Levels of inflammatory factors in maternal plasma were measured using a multiplex assay after an injection of low-dose lipopolysaccharide (LPS) to rats on gestational day (GD) 13.5. Following three additional daily LPS injections from GD14.5-16.5, GD17.5 placentas were harvested for HIF-1? immunolocalisation; serial sections were also stained for the hypoxia marker pimonidazole. A subset of rats received LPS injections along with GTN delivered continuously (25 ?g/h via a transdermal patch) on GD12.5-GD17.5.

Results

Within two hours of LPS administration, levels of maternal pro-inflammatory cytokines were increased compared with saline-treated controls. GD17.5 placentas of growth-restricted fetuses exhibited increased HIF-1? accumulation; however, this did not correlate with pimonidazole staining for which no differences were observed between groups. Furthermore, the LPS-mediated increases in maternal inflammatory cytokine levels and placental HIF-1? accumulation did not occur in rats treated with GTN.

Discussion

Our results demonstrate that inflammation-induced FGR is associated with increased placental HIF-1? accumulation; however, expression of this transcription factor may not correlate with regions of hypoxia in late-gestation placentas. The GTN-mediated attenuation of placental HIF-1? accumulation in LPS-treated rats provides insight into the mechanism by which GTN improves inflammation-induced complications of pregnancy.

SUBMITTER: Robb KP

PROVIDER: S-EPMC5397034 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Inflammation-induced fetal growth restriction in rats is associated with increased placental HIF-1α accumulation.

Robb Kevin P KP Cotechini Tiziana T Allaire Camille C Sperou Arissa A Graham Charles H CH

PloS one 20170419 4

<h4>Introduction</h4>Hypoxia-inducible factor 1-alpha (HIF-1α) is the oxygen-sensitive subunit of the transcription factor HIF-1, and its expression is increased in placentas from pregnancies complicated by pre-eclampsia (PE). Fetal growth restriction (FGR) and PE often share a common pathophysiology; however, it is unknown whether increased placental HIF-1α occurs in FGR. We previously demonstrated that aberrant maternal inflammation in rats resulted in altered utero-placental perfusion and FGR ...[more]

PMID: 28423052

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Project description:Fetal growth restriction (FGR) occurs when the fetus does not reach its genetically programmed intrauterine potential for growth and affects ~5‑10% of pregnancies. This condition is one of the leading causes of perinatal mortality and morbidity associated with obstetric and neonatal complications. Placental dysfunction in FGR causes an impairment in the transfer of nutrients and oxygen from the mother to the developing fetus. Maternal adaptations to placental insufficiency may also play a role in the pathophysiology of FGR. The present study aimed to compare the proteome of the placentas of 18 women with the physiological course of pregnancy and eutrophic fetus [estimated fetal weight (EFW) >10th percentile; control group] and 18 women with late FGR (EFW <10th percentile) diagnosed after 32 weeks of pregnancy, according to the Delphi consensus (study group). The U. Mann‑Whitney test was used to compare two independent groups. The R. Spearman correlation coefficient significance test was used to assess the existence of a relationship between the analyzed measurable parameters. P<0.05 was considered to indicate a statistically significant difference. The tests showed the presence of 356 different proteins which were responsible for the regulation of gene transcription control, inhibiting the activity of proteolytic enzymes, regulation of trophoblast proliferation and angiogenesis and inflammatory response. In the FGR placental proteome, other detected proteins were mostly involved in response to oxidative stress, cellular oxidation and detoxication, apoptosis, hemostatic and catabolic processes, energy transduction protein interactions, cell proliferation, differentiation and intracellular signaling. The present study used chromatographic mass‑spectrometry to compare the placental proteome profiles in pregnancies complicated by late‑onset FGR and normal pregnancy. Comparative analysis of proteomes from normal and FGR placentas showed significant differences. Further research is needed to clarify maternal and fetal adaptations to FGR.