Dynamic HIF1A Regulation During Human Placental Development1

Ietta, Francesca; Wu, Yunxin; Winter, Jennifer; Xu, Jin; Wang, Jinxia; Post, Martin; Caniggia, Isabella

doi:10.1095/biolreprod.106.051557

Cited by 106 publications

(97 citation statements)

References 38 publications

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“…Sections were counterstained with Carazzi's hematoxylin and mounted in Permount (Fisher Scientific; Unionville, ON). We have previously confirmed the specificity of all antibodies using human placental tissues (Ietta et al 2006).…”

Section: Ihcsupporting

confidence: 54%

Hypoxia-inducible Factors in the First Trimester Human Lung

Groenman

Rutter

Caniggia

et al. 2006

J Histochem Cytochem.

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Lung development takes place in a relatively low-oxygen environment, which is beneficial for lung organogenesis, including vascular development. Hypoxia-inducible factor (HIF)-1 plays an important role in mediating oxygen-regulated events. HIF-1 is stable and initiates gene transcription under hypoxia, whereas in normoxia, interaction with the von Hippel-Lindau (VHL) tumor suppressor protein leads to rapid degradation of the HIF-1α subunit. Interaction with VHL requires hydroxylation of HIF-1α proline residues by prolyl hydroxylases (PHDs). We investigated the expression of the various components regulating HIF-1α stability in first trimester (8-14 weeks) human lungs. Spatial expression was assessed by immunohistochemistry and temporal expression by quantitative PCR. Immunoreactivity for PHD1, PHD3, and seven in absentia homolog (SIAH) 1 was noted in the pulmonary epithelium. PHD2 was not expressed in the airway epithelium, but in the lung parenchyma. HIF-1α and vascular endothelial growth factor (VEGF) immunoreactivity were primarily detected in the branching epithelium. HIF-2α and ARNT proteins localized to the developing epithelium as well as mesenchymal, most likely vascular, structures in the parenchyma. VEGF receptor 2 (VEGFR2) was found in the subepithelium as well as in vascular structures of the mesenchyme. All components of the VEC complex (VHL, NEDD8, and Cullin2) were found in the epithelium. Quantitative PCR analysis demonstrated that VEGF, VEGFR1, HIF-1α, HIF-2α, ARNT, PHD1, PHD2, PHD3, and SIAH1 gene expression was constant during early pulmonary organogenesis. Cumulatively, the data suggest that the lung develops in a low-oxygen environment that allows for proper vascular development through HIF-regulated pathways.

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Section: Ihcsupporting

confidence: 54%

Hypoxia-inducible Factors in the First Trimester Human Lung

Groenman

Rutter

Caniggia

et al. 2006

J Histochem Cytochem.

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“…In the case of hypoxia, PHD activity decreased and HIF-1α rapidly gathered in the intracellular space, combined with β isoforms and was transferred to the nucleus to promote the transcription of hypoxia-responsive genes. Ietta et al (20) reported that HIF-1 was the key molecular component that mediated the regulation of hypoxia during trophoblast cell-associated invasion and differentiation processes. A previous study indicated that the expression levels of HIF-1α are sustained throughout pregnancy (21).…”

Section: Introductionmentioning

confidence: 99%

Expression and role of microRNA 18b and hypoxia inducible factor‑1α in placental tissues of preeclampsia patients

Wang

Weng

et al. 2017

Exp Ther Med

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Abstract. Abnormal expression of hypoxia inducible factor-1α (HIF-1α) is closely associated with various diseases. By detecting the mRNA and protein expression levels of microRNA 18b (miR-18b) and HIF-1α in placental tissues of preeclampsia (PE) patients and studying the effects of miR-18b on total cellular metabolic activity, migration and invasion in normal human trophoblast cell lines (HTR-8/SVneo), the present study aimed to investigate the effect of miR-18b on targeted regulation of HIF-1α and its clinical significance in the development of PE. Expression levels of miR-18b and HIF-1α mRNA in PE placental tissues were detected by reverse transcription-quantitative polymerase chain reaction and corresponding expression levels of HIF-1α protein were analyzed by western blotting. miR-18b overexpression and inhibited miR-18b expression in HTR-8/SVneo cells, which were constructed by transfecting miR-18b mimic and inhibitor, respectively, were investigated and the total cellular metabolic activity, migration and invasion abilities in different groups of cells were compared. Expression levels of miR-18b were significantly reduced in PE placental tissues and miR-18b inhibitor-transfected HTR-8/SVneo cells, whereas the expression levels of HIF-1α were significantly increased in PE placental tissues and significantly decreased in miR-18b mimic-transfected HTR-8/SVneo cells. Overexpression of miR-18b inhibited the expression of HIF-1α and reduced the cell invasion, migration and viability of HTR-8/SVneo cells. However, inhibition of miR-18b expression promoted the expression of HIF-1α and increased the cell invasion, migration and total cellular metabolic activity of HTR-8/SVneo cells. The present study indicated that abnormal expression of HIF-1α exhibited in PE placental tissues was regulated by miR-18b. Furthermore miR-18b expression was demonstrated to affect cell invasion, migration and viability through target regulation of HIF-1α. The results of the present study suggest that miR-18b and HIF-1α may have important roles in the development of PE.

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Section: Discussionmentioning

confidence: 99%

“…It was shown that HIF-1α and HIF-2α are expressed by villous cytotrophoblasts and syncytiotrophoblast, as well as extravillous cytotrophoblasts, and their expression in placenta decreases with gestational age [42,43]. It was suggested that the gestational age dependent reduction in HIFs likely reflects their degradation in response to increasing oxygen concentration [42,43]. In support of this premise is the finding of increased placental expression of HIF-1α and HIF-2α in pregnancies complicated by PE [44], which are also characterized by placental hypoxia [1,3,45].…”

Section: Discussionmentioning

confidence: 99%

Role of Hypoxia-Inducible Transcription Factors 1α and 2α in the Regulation of Plasminogen Activator Inhibitor-1 Expression in a Human Trophoblast Cell Line

2007

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The plasminogen activator inhibitors (PAIs) play critical roles in regulating hemostatic and invasive functions of trophoblasts through suppression of plasmin-dependent fibrinolysis and extracellular matrix degradation. The expression of PAI-1 is increased under hypoxic conditions, although the mechanism remains incompletely understood. In the current study we used HTR-8/SVneo cells, a first trimester extravillous trophoblast cell line, and siRNA technology to examine the role of hypoxia-inducible transcription factors (HIFs)−1α and −2α in the regulation of PAI-1 expression. Using serum-containing and serum-free media culture media it was initially noted that levels of PAI-1, but not PAI-2 protein, were markedly induced by hypoxic (2−3% oxygen) treatment. Under hypoxic conditions, Western blotting revealed that the presence of siRNAs to HIF-1α and HIF-2α suppressed expression of their respective proteins, whereas treatment with non-targeting and cyclophilin B siRNAs did not. Importantly, incubation with siRNA to HIF-1α or HIF-2α alone reduced PAI-1 protein levels to a similar extent, with the combined treatment inducing a more profound effect. The presence of HIF siRNAs reduced levels of PAI-1 mRNA as measured by quantitative real-time PCR, indicating that HIF-1α and HIF-2 α regulate PAI-1 expression at a transcriptional level. These results indicate that both HIF-1α and HIF-2α play important and similar roles in hypoxia-mediated stimulation of PAI-1 expression in HTR-8/SVneo cells. Our findings provide insight into the physiological regulation of trophoblast PAI-1 expression in early pregnancy when placental oxygen levels are low, as well as a mechanism for over-expression of placental PAI-1 noted in pregnancies with preeclampsia.

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Dynamic HIF1A Regulation During Human Placental Development1

Cited by 106 publications

References 38 publications

Hypoxia-inducible Factors in the First Trimester Human Lung

Hypoxia-inducible Factors in the First Trimester Human Lung

Expression and role of microRNA 18b and hypoxia inducible factor‑1α in placental tissues of preeclampsia patients

Role of Hypoxia-Inducible Transcription Factors 1α and 2α in the Regulation of Plasminogen Activator Inhibitor-1 Expression in a Human Trophoblast Cell Line

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