Dysregulation of Oxygen Sensing/Response Pathways in Pregnancies Complicated by Idiopathic Intrauterine Growth Restriction and Early-Onset Preeclampsia.
- Publisher:
- MDPI
- Publication Type:
- Journal Article
- Citation:
- Int J Mol Sci, 2022, 23, (5), pp. 2772
- Issue Date:
- 2022-03-02
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Full metadata record
| Field | Value | Language |
|---|---|---|
| dc.contributor.author | McCracken, SA | |
| dc.contributor.author | Seeho, SKM | |
| dc.contributor.author | Carrodus, T | |
| dc.contributor.author | Park, JH | |
| dc.contributor.author | Woodland, N | |
| dc.contributor.author | Gallery, EDM | |
| dc.contributor.author | Morris, JM | |
| dc.contributor.author | Ashton, AW | |
| dc.date.accessioned | 2023-06-30T21:04:58Z | |
| dc.date.available | 2022-03-01 | |
| dc.date.available | 2023-06-30T21:04:58Z | |
| dc.date.issued | 2022-03-02 | |
| dc.identifier.citation | Int J Mol Sci, 2022, 23, (5), pp. 2772 | |
| dc.identifier.issn | 1422-0067 | |
| dc.identifier.issn | 1422-0067 | |
| dc.identifier.uri | http://hdl.handle.net/10453/171050 | |
| dc.description.abstract | Preeclampsia (PE) and intrauterine growth restriction (IUGR) are the leading causes of maternal and fetal morbidity/mortality. The central deficit in both conditions is impaired placentation due to poor trophoblast invasion, resulting in a hypoxic milieu in which oxidative stress contributes to the pathology. We examine the factors driving the hypoxic response in severely preterm PE (n = 19) and IUGR (n = 16) placentae compared to the spontaneous preterm (SPT) controls (n = 13) using immunoblotting, RT-PCR, immunohistochemistry, proximity ligation assays, and Co-IP. Both hypoxia-inducible factor (HIF)-1α and HIF-2α are increased at the protein level and functional in pathological placentae, as target genes prolyl hydroxylase domain (PHD)2, PHD3, and soluble fms-like tyrosine kinase-1 (sFlt-1) are increased. Accumulation of HIF-α-subunits occurs in the presence of accessory molecules required for their degradation (PHD1, PHD2, and PHD3 and the E3 ligase von Hippel-Lindau (VHL)), which were equally expressed or elevated in the placental lysates of PE and IUGR. However, complex formation between VHL and HIF-α-subunits is defective. This is associated with enhanced VHL/DJ1 complex formation in both PE and IUGR. In conclusion, we establish a significant mechanism driving the maladaptive responses to hypoxia in the placentae from severe PE and IUGR, which is central to the pathogenesis of both diseases. | |
| dc.format | Electronic | |
| dc.language | eng | |
| dc.publisher | MDPI | |
| dc.relation.ispartof | Int J Mol Sci | |
| dc.relation.isbasedon | 10.3390/ijms23052772 | |
| dc.rights | info:eu-repo/semantics/openAccess | |
| dc.subject | 0399 Other Chemical Sciences, 0604 Genetics, 0699 Other Biological Sciences | |
| dc.subject.classification | Chemical Physics | |
| dc.subject.mesh | Female | |
| dc.subject.mesh | Fetal Growth Retardation | |
| dc.subject.mesh | Humans | |
| dc.subject.mesh | Hypoxia | |
| dc.subject.mesh | Hypoxia-Inducible Factor 1, alpha Subunit | |
| dc.subject.mesh | Infant, Newborn | |
| dc.subject.mesh | Oxygen | |
| dc.subject.mesh | Placenta | |
| dc.subject.mesh | Placentation | |
| dc.subject.mesh | Pre-Eclampsia | |
| dc.subject.mesh | Pregnancy | |
| dc.subject.mesh | Placenta | |
| dc.subject.mesh | Humans | |
| dc.subject.mesh | Fetal Growth Retardation | |
| dc.subject.mesh | Pre-Eclampsia | |
| dc.subject.mesh | Oxygen | |
| dc.subject.mesh | Pregnancy | |
| dc.subject.mesh | Placentation | |
| dc.subject.mesh | Infant, Newborn | |
| dc.subject.mesh | Female | |
| dc.subject.mesh | Hypoxia-Inducible Factor 1, alpha Subunit | |
| dc.subject.mesh | Hypoxia | |
| dc.subject.mesh | Female | |
| dc.subject.mesh | Fetal Growth Retardation | |
| dc.subject.mesh | Humans | |
| dc.subject.mesh | Hypoxia | |
| dc.subject.mesh | Hypoxia-Inducible Factor 1, alpha Subunit | |
| dc.subject.mesh | Infant, Newborn | |
| dc.subject.mesh | Oxygen | |
| dc.subject.mesh | Placenta | |
| dc.subject.mesh | Placentation | |
| dc.subject.mesh | Pre-Eclampsia | |
| dc.subject.mesh | Pregnancy | |
| dc.title | Dysregulation of Oxygen Sensing/Response Pathways in Pregnancies Complicated by Idiopathic Intrauterine Growth Restriction and Early-Onset Preeclampsia. | |
| dc.type | Journal Article | |
| utslib.citation.volume | 23 | |
| utslib.location.activity | Switzerland | |
| utslib.for | 0399 Other Chemical Sciences | |
| utslib.for | 0604 Genetics | |
| utslib.for | 0699 Other Biological Sciences | |
| pubs.organisational-group | /University of Technology Sydney | |
| pubs.organisational-group | /University of Technology Sydney/Faculty of Science | |
| pubs.organisational-group | /University of Technology Sydney/Faculty of Science/School of Life Sciences | |
| utslib.copyright.status | open_access | * |
| dc.date.updated | 2023-06-30T21:04:53Z | |
| pubs.issue | 5 | |
| pubs.publication-status | Published online | |
| pubs.volume | 23 | |
| utslib.citation.issue | 5 |
Abstract:
Preeclampsia (PE) and intrauterine growth restriction (IUGR) are the leading causes of maternal and fetal morbidity/mortality. The central deficit in both conditions is impaired placentation due to poor trophoblast invasion, resulting in a hypoxic milieu in which oxidative stress contributes to the pathology. We examine the factors driving the hypoxic response in severely preterm PE (n = 19) and IUGR (n = 16) placentae compared to the spontaneous preterm (SPT) controls (n = 13) using immunoblotting, RT-PCR, immunohistochemistry, proximity ligation assays, and Co-IP. Both hypoxia-inducible factor (HIF)-1α and HIF-2α are increased at the protein level and functional in pathological placentae, as target genes prolyl hydroxylase domain (PHD)2, PHD3, and soluble fms-like tyrosine kinase-1 (sFlt-1) are increased. Accumulation of HIF-α-subunits occurs in the presence of accessory molecules required for their degradation (PHD1, PHD2, and PHD3 and the E3 ligase von Hippel-Lindau (VHL)), which were equally expressed or elevated in the placental lysates of PE and IUGR. However, complex formation between VHL and HIF-α-subunits is defective. This is associated with enhanced VHL/DJ1 complex formation in both PE and IUGR. In conclusion, we establish a significant mechanism driving the maladaptive responses to hypoxia in the placentae from severe PE and IUGR, which is central to the pathogenesis of both diseases.
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