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Hypoxia and Preeclampsia: Increased Expression of Urocortin 2 and Urocortin 3

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Abstract

Objective

Urocortin 2 (Ucn2) and urocortin 3 (Ucn3) are new members of the corticotrophin-releasing hormone (CRH) family of peptides expressed and localized in human placenta. In the current study, we aimed to asses whether hypoxia affects placental Ucn2/Ucn3 messenger RNA (mRNA) expression and protein localization in physiological or pathological hypoxia and to evaluate whether the effect is modulated by the hypoxia-inducible factor 1α (HIF-1α).

Methods

Early first-trimester placental specimens from elective termination of pregnancy were used for villous explants and term placental tissue were used for primary cell cultures. The samples were incubated under different oxygen conditions; parallel sets exposed to hypoxia re-oxygenation (HR). Dimethyloxalylglycine (DMOG), an HIF-1α stabilizer, was used to mimic the effects of hypoxia in villous explants. Real-time polymerase chain reaction (PCR) and immunohystochemistry were performed on early pregnancy and preeclamptic (PE) placentae. mRNA levels were measured on villous explants and cell cultures incubated under different oxygen and reagent conditions.

Results

Both Ucn2 and Ucn3 mRNA expression was significantly higher at 6 to 9 weeks of gestation than 10 to 12 wks and in primary trophoblast cell cultures and explants exposed to low O2 tension (3%) compared to 20% O2. Strong Ucn2/Ucn3 immunoreactivity was present in trophoblast villi from 6 weeks placentae. Ucn2 immunostaining was stronger in early PE (E-PE) samples relative to controls whereas Ucn3 showed stronger immunoreactivity in late-PE (L-PE) placentae. Only Ucn2 transcript levels increased in HR explants. Ucn2 and Ucn3 expression by first-trimester explants was significantly greater in the presence of DMOG. All PE placentae expressed significantly higher Ucn2 and Ucn3 mRNA compared to controls.

Discussion

Placental Ucn2 and Ucn3 expression is sensitive to O2 tensions and mediated by HIF-1α. During early pregnancy, Ucn2/Ucn3 may influence trophoblast proliferation and establishment of pregnancy. In PE placentae, the increased expression of both peptides may reflect a response to the oxidative stress.

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Authors and Affiliations

  1. Department of Physiology, Obstetrics and Gynecology and Medicine, University of Toronto, Canada

    Alberto Imperatore PhD, MD, John R G Challis PhD & Isabella Caniggia PhD, MD

  2. Department of Pediatrics, Obstetrics, and Reproductive Medicine, Obstetrics and Gynaecology, University of Siena, Policlinico S.Maria delle Scotte, Siena, Italy

    Alberto Imperatore PhD, MD & Felice Petraglia MD

  3. Department of Obstetrics and Gynecology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada

    Alessandro Rolfo PhD & Isabella Caniggia PhD, MD

Authors
  1. Alberto Imperatore PhD, MD
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  2. Alessandro Rolfo PhD
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  3. Felice Petraglia MD
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  4. John R G Challis PhD
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  5. Isabella Caniggia PhD, MD
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Correspondence to Alberto Imperatore PhD, MD.

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Imperatore, A., Rolfo, A., Petraglia, F. et al. Hypoxia and Preeclampsia: Increased Expression of Urocortin 2 and Urocortin 3. Reprod. Sci. 17, 833–843 (2010). https://doi.org/10.1177/1933719110373147

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