Energy status and HIF signalling in chorionic villi show no evidence of hypoxic stress during human early placental development.
Early human placental and embryonic development occurs in a physiologically low oxygen environment supported by histiotrophic secretions from endometrial glands. In this study, we compare the placental metabolomic profile in the first, second and third trimesters to determine whether the energy demands are adequately met in the first trimester. We investigated whether hypoxia-inducible factors, HIF-1α and/or HIF-2α, might regulate transcription during the first trimester. First and second trimester tissue was collected using a chorionic villus sampling-like (CVS) technique. Part of each villus sample was frozen immediately and the remainder cultured under 2 or 21% O2 ± 1 mM H2O2, and ±the p38 MAPK pathway inhibitor, PD169316. Levels of HIF-1α were assessed by western blotting and VEGFA, PlGF and GLUT3 transcripts were quantified by RT-PCR. Term samples were collected from normal elective Caesarean deliveries. There were no significant differences in concentrations of ADP, NAD(+), lactate, and glucose, and in the ATP/ADP ratio, across gestational age. Neither HIF-1α nor HIF-2α could be detected in time-zero CVS samples. However, culture under any condition (2 or 21% O2 ± 1 mM H2O2) increased HIF-1α and HIF-2α. HIF-1α and HIF-2α were additionally detected in specimens retrieved after curettage. HIF-1α stabilization was accompanied by significant increases in VEGFA and GLUT3 and a decrease in PlGF mRNAs. These effects were suppressed by PD169316. In conclusion, our data suggest that first trimester placental tissues are not energetically compromised, and that HIF-1α is unlikely to play an appreciable role in regulating transcriptional activity under steady-state conditions in vivo. However, the pathway may be activated by stress conditions.
Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK.
T
T
Cindrova-Davies
Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK.
M Tissot
MT
van Patot
Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK.
L
L
Gardner
Academic Department of Obstetrics and Gynaecology, Royal Free and University College, London, UK.
E
E
Jauniaux
Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK gjb2@cam.ac.uk.
G J
GJ
Burton
Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge CB2 0SW, UK National Institute for Health Research, Cambridge Comprehensive Biomedical Research Centre, Cambridge, UK.
D S
DS
Charnock-Jones
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D002824:Chorionic Villi / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects* / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental; D051274:Glucose Transporter Type 3 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology*; D010929:Placentation / Q000502:physiology; D011247:Pregnancy; D011264:Pregnancy Trimesters; D061251:Primary Cell Culture; D015398:Signal Transduction; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D051792:Basic Helix-Loop-Helix Proteins; D051274:Glucose Transporter Type 3; D006861:Hydrogen Peroxide; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007093:Imidazoles; D008565:Membrane Proteins; D010100:Oxygen; D042461:Vascular Endothelial Growth Factor A; D048051:p38 Mitogen-Activated Protein Kinases; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C098069:PIGF protein, human; C495687:SLC2A3 protein, human; C467484:VEGFA protein, human; C408604:2-(4-nitrophenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazole
HIF-1α; energy status; first trimester; metabolomics; placenta