Abnormalities in Oxygen Sensing Define Early and Late Onset Preeclampsia as Distinct Pathologies
Open accessAbstract
BACKGROUND: The pathogenesis of preeclampsia, a serious pregnancy disorder, is still elusive and its treatment empirical. Hypoxia Inducible Factor-1 (HIF-1) is crucial for placental development and early detection of aberrant regulatory mechanisms of HIF-1 could impact on the diagnosis and management of preeclampsia. HIF-1α stability is controlled by O(2)-sensing enzymes including prolyl hydroxylases (PHDs), Factor Inhibiting HIF (FIH), and E3 ligases Seven In Absentia Homologues (SIAHs). Here we investigated early- (E-PE) and late-onset (L-PE) human preeclamptic placentae and their ability to sense changes in oxygen tension occurring during normal placental development. METHODS AND FINDINGS: Expression of PHD2, FIH and SIAHs were significantly down-regulated in E-PE compared to control and L-PE placentae, while HIF-1α levels were increased. PHD3 expression was increased due to decreased FIH levels as demonstrated by siRNA FIH knockdown experiments in trophoblastic JEG-3 cells. E-PE tissues had markedly diminished HIF-1α hydroxylation at proline residues 402 and 564 as assessed with monoclonal antibodies raised against hydroxylated HIF-1α P402 or P564, suggesting regulation by PHD2 and not PHD3. Culturing villous explants under varying oxygen tensions revealed that E-PE, but not L-PE, placentae were unable to regulate HIF-1α levels because PHD2, FIH and SIAHs did not sense a hypoxic environment. CONCLUSION: Disruption of oxygen sensing in E-PE vs. L-PE and control placentae is the first molecular evidence of the existence of two distinct preeclamptic diseases and the unique molecular O(2)-sensing signature of E-PE placentae may be of diagnostic value when assessing high risk pregnancies and their severity.
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Aberrant HIF signaling has been implicated in the pathophysiology of pre-eclampsia, in particular the early-onset form when the PHDs do not appear to sense oxygen, and may be responsible for abnormal placental secretion of angiogenic regulatory factors.
“Aberrant HIF signaling has been implicated in the pathophysiology of pre-eclampsia, in particular of the early-onset form when the PHDs do not appear to sense oxygen (90, 448, 467), and may be responsible for the abnormal placental secretion of angiogenic regulatory factors that is thought to precipitate the clinical syndrome (413).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [467]
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Self-citation
- Authors
- Rolfo, A., Many, A., Racano, A., Tal, R., Tagliaferro, A., Ietta, F., Wang, J., Post, M., & Caniggia, I.
- Affiliations
- Mount Sinai Hospital (CA)
- Hospital for Sick Children (CA)
- University of Toronto (CA)
- Corresponding author
- Caniggia, Isabella
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-10-12
- Volume
- 5
- Issue
- 10
- Pages
- e13288
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2953500
- OpenAlex
- W2006347607
- Cited by
- 112
- References
- 75
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 6 · 2023: 6 · 2022: 8 · 2021: 8 · 2020: 4 · 2019: 8 · 2018: 5 · 2017: 8 · 2016: 6 · 2015: 6 · 2014: 12 · 2013: 11 · 2012: 12
- FWCI
- 11.78
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Use Siena air (University of Siena) (submittedVersion)
- Funders
- Canadian Institutes of Health Research (MOP-14096, -14096)
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Neonatal and fetal brain pathology
- Health Sciences › Medicine › Psychiatry and Mental health › Neurological Complications and Syndromes
- Keywords
- preeclampsia, early-onset preeclampsia, late-onset preeclampsia, oxygen sensing, HIF-1, HIF-1α hydroxylation, prolyl hydroxylase 2, prolyl hydroxylase 3, factor inhibiting HIF, placenta, hypoxia, preeclampsia diagnosis, high-risk pregnancy
- MeSH terms
- Adult, Base Sequence, Cell Line, Female, Humans, Oxygen, Pre-Eclampsia, Pregnancy, Blotting, Western, In Situ Hybridization, DNA Primers, Reverse Transcriptase Polymerase Chain Reaction, Gene Silencing, RNA, Small Interfering
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