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Dynamic HIF1A Regulation During Human Placental Development1
Abstract
The human placenta is a unique organ in terms of oxygenation as it undergoes a transition from a low to a more oxygenated environment. This physiological switch in oxygen tension is a prerequisite for proper placental development and involves the hypoxia inducible factor (HIF). HIF is stable and initiates gene transcription under hypoxia, whereas in normoxia, interaction with the von Hippel-Lindau tumor suppressor protein (VHL) leads to rapid degradation of the HIF1A subunit. The degradation requires formation of a multiprotein complex (VHLCBC) and hydroxylation of HIF1A proline residues via members of the egg-laying-defective nine (EGLN) family. Herein, we have investigated the regulatory mechanisms of HIF1A expression during human placental development. Expression of HIF1A and VHL was high at 7-9 wk of gestation, when oxygen tension is low, and decreased when placental oxygen tension increases (10-12 wk of gestation). During early placentation, HIF1A localized in cytotrophoblasts, while VHL was present in syncytiotrophoblasts. At 10-12 wk, VHL appeared in cytotrophoblast cells, which coincided with the disappearance of HIF1A. At the same time the association of VHL and Cullin 2 as well as ubiquitination of HIF1A was maximal. EGLN1, EGLN2, and EGLN3 were also temporally expressed in an oxygen-dependent fashion, with greatest mRNA expression at 10-12 wk of gestation. Inhibition of EGLN activity increased HIF1A stability in villous explants and stimulated transforming growth factor beta 3 (TGFB3) expression consistent with promoter analyses showing that HIF1A transactivates TGFB3. These data demonstrate that during placental development, HIF1A is regulated by temporal and spatial changes in expression and association of molecules forming the multi-protein VHLCBC complex as well as prolyl hydroxylase activities.
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“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 [269]
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Metadata
- Authors
- Ietta, F., Wu, Y., Winter, J., Xu, J., Wang, J., Post, M., & Caniggia, I.
- Affiliations
- Mount Sinai Hospital (CA)
- University of Toronto (CA)
- Corresponding author
- Caniggia, Isabella
- Venue
- Biology of Reproduction
- Publisher
- Oxford University Press (OUP)
- Published
- 2006-07-01
- Volume
- 75
- Issue
- 1
- Pages
- 112-121
- ISSN
- 0006-3363 (ISSN-L)
- 1529-7268
- OpenAlex
- W2097321304
- Cited by
- 127
- References
- 41
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 6 · 2023: 7 · 2022: 3 · 2021: 7 · 2020: 6 · 2019: 4 · 2018: 6 · 2017: 12 · 2016: 7 · 2015: 6 · 2014: 9 · 2013: 6 · 2012: 7
- FWCI
- 5.52
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biology of Reproduction (publishedVersion)
- PubMed (publishedVersion)
- BioOne Complete (BioOne) (submittedVersion)
- Use Siena air (University of Siena) (submittedVersion)
- Funders
- Canada Research Chairs
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Keywords
- HIF1A, hypoxia, von Hippel-Lindau protein, prolyl hydroxylase, CUL2, ubiquitination, oxygen partial pressure, cytotrophoblast, syncytiotrophoblast, transforming growth factor-beta3
- MeSH terms
- Hypoxia, Female, Humans, Nuclear Proteins, Organ Culture Techniques, Oxygen, Placenta, Placentation, Pregnancy, Procollagen-Proline Dioxygenase, Transfection, Trophoblasts, Transcriptional Activation, Transforming Growth Factor beta, Dioxygenases, Aryl Hydrocarbon Receptor Nuclear Translocator, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit, Transforming Growth Factor beta3, Hypoxia-Inducible Factor-Proline Dioxygenases
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