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Oxygen Regulation of Placental 11ß-Hydroxysteroid Dehydrogenase 2: Physiological and Pathological Implications

Departments of Physiology (N.A., S.G., C.D., I.C., J.R.G.C.) and Obstetrics and Gynecology (I.C., J.R.G.C.), Canadian Institutes for Health Research Group in Development and Fetal Health, and Program in Development and Fetal Health, Samuel Lunenfeld Research Institute, Mt. Sinai Hospital (C.D., I.C., J.R.G.C.), University of Toronto Toronto, Ontario, Canada M5S 1A8

Address all correspondence and requests for reprints to: Dr. Nadia Alfaidy, Department of Physiology, University of Toronto, 1 King’s College Circle, Toronto, Ontario, Canada M5S 1A8. E-mail: n.alfaidy{at}utoronto.ca.

Abstract

Preeclampsia (PE) is a major cause of maternal and perinatal morbidity and mortality. The genesis of PE is related to deficient trophoblast invasion of maternal spiral arteries, which might result in a reduction of placental (PL) oxygen (O₂). An absence of increased O₂ that normally occurs around the 10–12th wk of gestation results in aberrant expression of genes that might contribute to the pathophysiology of PE. We examined the expression and regulation of PL 11ß-hydroxysteroid dehydrogenase 2 (11ß-HSD) in normal pregnancies and in PE. Two types of 11ß-HSD exist in the placenta, 11ß-HSD1 and 11ß-HSD2. 11ß-HSD2 is thought to protect the fetus from cortisol excess. In PE, both the expression and activity of PL 11ß-HSD2 were reduced significantly compared with those in age-matched controls. As PE is associated with a reduction of PL O₂, we next investigated whether in normal pregnancy 11ß-HSD2 expression changes at the time of the increase in O₂. 11ß-HSD2 was detected as early as 5 wk, with expression limited to the syncytiotrophoblast (ST). At 10–12 wk, this expression increased and was also found in the cytotrophoblast and extravillous trophoblast. These results were substantiated by Western blot. The ability of O₂ to regulate 11ß-HSD2 was determined both in cultures of villous explant from early gestation and in term trophoblast cells after incubation under 3% or 20% O₂. Villous explants cultured under 20% O₂ showed higher enzyme activity and expression compared with 3% O₂. Term trophoblast cells also exhibited higher enzyme activity at 20% vs. 3% O₂. No change in 11ß-HSD1 expression was observed in early pregnancy or in PE. This is the first report to suggest that 11ß-HSD2 is O₂ dependent in first and third trimester placenta during human gestation.

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