PMID- 28423052
OWN - NLM
STAT- MEDLINE
DCOM- 20170427
LR  - 20211201
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 12
IP  - 4
DP  - 2017
TI  - Inflammation-induced fetal growth restriction in rats is associated with 
      increased placental HIF-1alpha accumulation.
PG  - e0175805
LID - 10.1371/journal.pone.0175805 [doi]
LID - e0175805
AB  - INTRODUCTION: Hypoxia-inducible factor 1-alpha (HIF-1alpha) 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-1alpha 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-1alpha accumulation and whether GTN administration could prevent 
      increases in placental HIF-1alpha. 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-1alpha immunolocalisation; serial sections were also stained for 
      the hypoxia marker pimonidazole. A subset of rats received LPS injections along 
      with GTN delivered continuously (25 mug/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-1alpha 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-1alpha accumulation did not occur in rats treated with GTN. DISCUSSION: Our 
      results demonstrate that inflammation-induced FGR is associated with increased 
      placental HIF-1alpha 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-1alpha accumulation in LPS-treated rats 
      provides insight into the mechanism by which GTN improves inflammation-induced 
      complications of pregnancy.
FAU - Robb, Kevin P
AU  - Robb KP
AD  - Department of Biomedical and Molecular Sciences, Queen's University, Kingston, 
      Ontario, Canada.
FAU - Cotechini, Tiziana
AU  - Cotechini T
AD  - Department of Biomedical and Molecular Sciences, Queen's University, Kingston, 
      Ontario, Canada.
FAU - Allaire, Camille
AU  - Allaire C
AD  - Department of Biomedical and Molecular Sciences, Queen's University, Kingston, 
      Ontario, Canada.
FAU - Sperou, Arissa
AU  - Sperou A
AD  - Department of Biomedical and Molecular Sciences, Queen's University, Kingston, 
      Ontario, Canada.
FAU - Graham, Charles H
AU  - Graham CH
AD  - Department of Biomedical and Molecular Sciences, Queen's University, Kingston, 
      Ontario, Canada.
LA  - eng
PT  - Journal Article
DEP - 20170419
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Hif1a protein, rat)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Interleukin-6)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 130068-27-8 (Interleukin-10)
RN  - EC 2.7.10.1 (Flt1 protein, rat)
RN  - EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-1)
RN  - G59M7S0WS3 (Nitroglycerin)
SB  - IM
MH  - Animals
MH  - Disease Models, Animal
MH  - Female
MH  - Fetal Growth Retardation/chemically induced/*immunology/pathology/prevention & 
      control
MH  - Gene Expression Regulation
MH  - Gestational Age
MH  - Humans
MH  - Hypoxia/chemically induced/*immunology/pathology/prevention & control
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*immunology
MH  - Inflammation
MH  - Interleukin-10/genetics/immunology
MH  - Interleukin-6/genetics/immunology
MH  - Lipopolysaccharides/administration & dosage
MH  - Nitroglycerin/pharmacology
MH  - Placenta/drug effects/*immunology/pathology
MH  - Pre-Eclampsia/chemically induced/*immunology/pathology/prevention & control
MH  - Pregnancy
MH  - Rats
MH  - Rats, Wistar
MH  - Signal Transduction
MH  - Transdermal Patch
MH  - Tumor Necrosis Factor-alpha/genetics/immunology
MH  - Vascular Endothelial Growth Factor Receptor-1/genetics/immunology
PMC - PMC5397034
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2017/04/20 06:00
MHDA- 2017/04/28 06:00
PMCR- 2017/04/19
CRDT- 2017/04/20 06:00
PHST- 2016/07/03 00:00 [received]
PHST- 2017/03/31 00:00 [accepted]
PHST- 2017/04/20 06:00 [entrez]
PHST- 2017/04/20 06:00 [pubmed]
PHST- 2017/04/28 06:00 [medline]
PHST- 2017/04/19 00:00 [pmc-release]
AID - PONE-D-16-26639 [pii]
AID - 10.1371/journal.pone.0175805 [doi]
PST - epublish
SO  - PLoS One. 2017 Apr 19;12(4):e0175805. doi: 10.1371/journal.pone.0175805. 
      eCollection 2017.