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Abnormalities in Oxygen Sensing Define Early and Late Onset Preeclampsia as Distinct Pathologies
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 managemen...
Autores principales: | , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2010
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2953500/ https://www.ncbi.nlm.nih.gov/pubmed/20967267 http://dx.doi.org/10.1371/journal.pone.0013288 |
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author | Rolfo, Alessandro Many, Ariel Racano, Antonella Tal, Reshef Tagliaferro, Andrea Ietta, Francesca Wang, Jinxia Post, Martin Caniggia, Isabella |
author_facet | Rolfo, Alessandro Many, Ariel Racano, Antonella Tal, Reshef Tagliaferro, Andrea Ietta, Francesca Wang, Jinxia Post, Martin Caniggia, Isabella |
author_sort | Rolfo, Alessandro |
collection | PubMed |
description | 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. |
format | Text |
id | pubmed-2953500 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-29535002010-10-21 Abnormalities in Oxygen Sensing Define Early and Late Onset Preeclampsia as Distinct Pathologies Rolfo, Alessandro Many, Ariel Racano, Antonella Tal, Reshef Tagliaferro, Andrea Ietta, Francesca Wang, Jinxia Post, Martin Caniggia, Isabella PLoS One Research Article 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. Public Library of Science 2010-10-12 /pmc/articles/PMC2953500/ /pubmed/20967267 http://dx.doi.org/10.1371/journal.pone.0013288 Text en Rolfo et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Rolfo, Alessandro Many, Ariel Racano, Antonella Tal, Reshef Tagliaferro, Andrea Ietta, Francesca Wang, Jinxia Post, Martin Caniggia, Isabella Abnormalities in Oxygen Sensing Define Early and Late Onset Preeclampsia as Distinct Pathologies |
title | Abnormalities in Oxygen Sensing Define Early and Late Onset Preeclampsia as Distinct Pathologies |
title_full | Abnormalities in Oxygen Sensing Define Early and Late Onset Preeclampsia as Distinct Pathologies |
title_fullStr | Abnormalities in Oxygen Sensing Define Early and Late Onset Preeclampsia as Distinct Pathologies |
title_full_unstemmed | Abnormalities in Oxygen Sensing Define Early and Late Onset Preeclampsia as Distinct Pathologies |
title_short | Abnormalities in Oxygen Sensing Define Early and Late Onset Preeclampsia as Distinct Pathologies |
title_sort | abnormalities in oxygen sensing define early and late onset preeclampsia as distinct pathologies |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2953500/ https://www.ncbi.nlm.nih.gov/pubmed/20967267 http://dx.doi.org/10.1371/journal.pone.0013288 |
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