Oxygen regulation of placental 11β-hydroxysteroid dehydrogenase 2: Physiological and pathological implications

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 (O 2). An absence of increased O 2 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 11β-hydroxysteroid dehydrogenase 2 (11β-HSD) in normal pregnancies and in PE. Two types of 11β-HSD exist in the placenta, 11β-HSD1 and 11β-HSD2. 11β-HSD2 is thought to protect the fetus from cortisol excess. In PE, both the expression and activity of PL 11β-HSD2 were reduced significantly compared with those in age-matched controls. As PE is associated with a reduction of PL O 2, we next investigated whether in normal pregnancy 11β-HSD2 expression changes at the time of the increase in O 2. 11β-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 O 2 to regulate 11β-HSD2 was determined both in cultures of villous explant from early gestation and in term trophoblast cells after incubation under 3% or 20% O 2. Villous explants cultured under 20% O 2 showed higher enzyme activity and expression compared with 3% O 2. Term trophoblast cells also exhibited higher enzyme activity at 20% vs. 3% O 2. No change in 11βHSD1 expression was observed in early pregnancy or in PE. This is the first report to suggest that 11β-HSD2 is O 2 dependent in first and third trimester placenta during human gestation.