Expression, Ontogeny, and Regulation of Hypoxia-Inducible Transcription Factors in the Human Placenta1
Abstract
Placental hypoxia likely plays an important role in both normal placental development and pathology. Yet, the molecular mechanisms of hypoxia signaling in this organ are virtually unexplored. Therefore, we investigated the expression of the hypoxia inducible transcription factors (HIF) in normal human placentas spanning the first trimester to term. Several key observations emerged: 1) HIF-1 alpha and -2 alpha mRNA were present in placentas of all gestational ages but with greater variability during early pregnancy; 2) overall, HIF-1 alpha mRNA was expressed at a constant level in all placentas, whereas HIF-2 alpha mRNA increased significantly with gestational age; 3) both HIF-1 alpha and -2 alpha protein decreased significantly with gestational age; and 4) HIF-1 alpha and -2 alpha immunoreactivity were overlapping in cellular distribution being expressed by the syncytiotrophoblast, villous cytotrophoblast, and fetoplacental vasculature with both nuclear and cytoplasmic localization. Next, we studied the regulation of these transcription factors by oxygen using placental villous explants in culture from first-trimester and term placentas. The major findings were 1) HIF-1 alpha and -2 alpha protein, but not mRNA, was induced by hypoxia in the placental villous explants; 2) HIF-1 alpha DNA-binding activity was also stimulated by hypoxia; and 3) glucose transporter-1 mRNA (a known target of HIF) was also increased by hypoxia in placental villous explants. We suggest that physiological hypoxia contributes to the increased expression of HIF-1 alpha and -2 alpha protein in early placentas and that regulation of these transcription factors by hypoxia in the human placenta occurs at the level of protein and not mRNA.
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HIF-1 and HIF-2 have been immunolocalized in the human placenta to the trophoblast and endothelial cells throughout gestation.
“Consistent with these effects, HIF-1 and HIF-2 have been immunolocalized in the human placenta to the trophoblast and endothelial cells throughout gestation (447).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [447]
Ontogenetic studies have reported contrasting results, with peaks of HIF-1α at 7-10 weeks and then again at 14-18 weeks, or a steady decline in HIF-1α from 5-8 weeks to 18-21 weeks and a rapid decline of HIF-2α between 5-8 weeks and 9-11 weeks.
“Ontogenetic studies have reported contrasting results, with peaks of HIF-1α at 7-10 weeks and then again at 14-18 weeks (269), or a steady decline in HIF-1α from 5-8 weeks to 18-21 weeks and a rapid decline of HIF-2α between 5-8 weeks and 9-11 weeks (447).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [447]
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- Authors
- Rajakumar, A., & Conrad, K. P.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Conrad, Kirk P.
- Venue
- Biology of Reproduction
- Publisher
- Oxford University Press (OUP)
- Published
- 2000-08-01
- Volume
- 63
- Issue
- 2
- Pages
- 559-569
- ISSN
- 0006-3363 (ISSN-L)
- 1529-7268
- OpenAlex
- W2106782975
- Cited by
- 177
- References
- 44
- Citations by year
- 2026: 3 · 2025: 3 · 2023: 10 · 2022: 3 · 2021: 9 · 2020: 5 · 2019: 2 · 2018: 5 · 2017: 10 · 2016: 7 · 2015: 7 · 2014: 11 · 2013: 8 · 2012: 11
- FWCI
- 7.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biology of Reproduction (publishedVersion)
- PubMed (publishedVersion)
- BioOne Complete (BioOne) (submittedVersion)
- Funders
- National Institutes of Health (5k04hd001098-02, 5r01hl056410-03)
- National Heart, Lung, and Blood Institute (R01 HL 56410)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01-HD30367, P01HD030367, KO4 HD01098)
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- hypoxia-inducible factor, HIF-1α, placental hypoxia, human placenta, placental development, gestational age, syncytiotrophoblast, cytotrophoblast, placental vasculature, hypoxia signaling, glucose transporter 1, DNA-binding activity, placental villi
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Hypoxia, DNA, DNA-Binding Proteins, Female, Gene Expression Regulation, Gestational Age, Humans, Immunohistochemistry, Nuclear Proteins, Peptide Initiation Factors, Placenta, Pregnancy, RNA, Messenger, Transcription Factors, Signal Transduction, Cell Hypoxia, Culture Techniques, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit
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