Hypoxia-inducible factor-1 mediates the biological effects of oxygen on human trophoblast differentiation through TGFβ3
Open accessAbstract
During early pregnancy, placentation occurs in a relatively hypoxic environment that is essential for appropriate embryonic development. Intervillous blood flow increases around 10 to 12 weeks of gestation and results in exposure of trophoblast cells to increased oxygen tension. Before this time, low oxygen appears to prevent trophoblast differentiation toward an invasive phenotype. Using human villous explants of 5-8 weeks' gestation, we found that low oxygen tension triggered trophoblast proliferation, fibronectin synthesis, alpha(5) integrin expression, and gelatinase A activity. These biochemical markers were barely detectable under oxic conditions. We therefore examined the placental expression of hypoxia-inducible factor-1 (HIF-1), a master regulator of oxygen homeostasis, and determined that expression of HIF-1alpha subunit during the first trimester of gestation parallels that of TGFbeta(3), an inhibitor of extravillous trophoblast differentiation. Expression of both molecules is high in early pregnancy and falls around 9 weeks of gestation, when placental pO(2) levels are believed to increase. Increasing oxygen tension induced a similar decrease in expression in cultured explants. Moreover, antisense inhibition of HIF-1alpha expression in hypoxic explants inhibited expression of TGFbeta(3), arrested cell proliferation, decreased alpha(5) expression and gelatinase A activity, and triggered biochemical markers of an invasive trophoblast phenotype such as alpha(1) integrin and gelatinase B expression. These data suggest that the oxygen-regulated early events of trophoblast differentiation are in part mediated by TGFbeta(3) through HIF-1 transcription factors.
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Experiments on first trimester placental explants cultured at 3% oxygen compared with 21% indicate that HIF regulates trophoblast proliferation, migration and invasion through its actions on TGFß3.
“Experiments on first trimester placental explants cultured at 3% oxygen compared with 21% indicate that HIF regulates trophoblast proliferation, migration and invasion through its actions on TGFß3 (89).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [89]
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Self-citation
- Authors
- Caniggia, I., Mostachfi, H., Winter, J., Gassmann, M., Lye, S. J., Kuliszewski, M., & Post, M.
- Affiliations
- University of Toronto (CA)
- Mount Sinai Hospital (CA)
- University of Zurich (CH)
- Corresponding author
- Caniggia, Isabella
- Venue
- Journal of Clinical Investigation
- Published
- 2000-03-01
- Volume
- 105
- Issue
- 5
- Pages
- 577-587
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC289179
- OpenAlex
- W2102277066
- Cited by
- 644
- References
- 48
- Citations by year
- 2026: 17 · 2025: 16 · 2024: 15 · 2023: 17 · 2022: 21 · 2021: 22 · 2020: 22 · 2019: 19 · 2018: 26 · 2017: 26 · 2016: 21 · 2015: 24 · 2014: 18 · 2013: 27 · 2012: 20
- FWCI
- 41.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical Research Council Canada
- Medical Research Council (14096)
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Gestational Trophoblastic Disease Studies
- Keywords
- HIF-1, HIF-1α, TGF-beta3, trophoblast differentiation, extravillous trophoblast invasion, oxygen partial pressure, placental hypoxia, trophoblast proliferation, fibronectin, integrin alpha5, MMP-2, MMP-9, integrin alpha1, placenta, early pregnancy
- MeSH terms
- Hypoxia, Cell Differentiation, DNA-Binding Proteins, Female, Fibronectins, Gene Expression Regulation, Gestational Age, Humans, Immunohistochemistry, Nuclear Proteins, Oxygen, Placenta, Pregnancy, RNA, Messenger, Transcription Factors, Trophoblasts, Transforming Growth Factor beta, Oligonucleotides, Antisense, In Situ Hybridization, Gelatinases, Culture Techniques, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit
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