Abstract
BackgroundThe 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 O2-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 FindingsExpression 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.ConclusionDisruption 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 O2-sensing signature of E-PE placentae may be of diagnostic value when assessing high risk pregnancies and their severity.
Highlights
Preeclampsia is a placental disorder that affects about 5–10% of all pregnancies and clinically manifests itself in the third trimester with a wide variety of maternal symptoms, including hypertension, proteinuria, and generalized edema [1,2]
Disruption of oxygen sensing in E-PE vs. late-onset preeclampsia (L-PE) and control placentae is the first molecular evidence of the existence of two distinct preeclamptic diseases and the unique molecular O2-sensing signature of E-PE placentae may be of diagnostic value when assessing high risk pregnancies and their severity
Villous explants from early onset (E-PE) and late onset (L-PE) preeclamptic placentae and explants exposed at 3% and 20% O2 as determined by real-time PCR analysis. (B) Immunohistochemical analysis of hypoxia-inducible family (HIF)-1a protein on sections of E-PE (n = 5) and PTC (n = 3) explants exposed at 3% and 20% O2
Summary
Preeclampsia is a placental disorder that affects about 5–10% of all pregnancies and clinically manifests itself in the third trimester with a wide variety of maternal symptoms, including hypertension, proteinuria, and generalized edema [1,2]. The placenta plays a key role in the genesis of this disease as its removal at the time of delivery results in rapid resolution of the clinical symptoms. Preeclampsia appears suddenly in the third trimester, the initial insult underlying its genesis occurs likely in the first trimester of pregnancy, at the time when trophoblast cell differentiation/ invasion commences. 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
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