Endocrine Abstracts (2002) 3 P221

Oxygen tension regulates placental 11 beta-hydroxysteroid dehydrogenase type 2

PM Driver1, M Hewison1, MD Kilby2 & PM Stewart1

1Division of Medical Sciences, University of Birmingham, Birmingham, UK; 2Division of Reproductive and Child Health, University of Birmingham, Birmingham, UK.

11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) is responsible for the conversion of hormonally active cortisol (F) to inactive cortisone (E), and is expressed in mineralocorticoid target tissues (kidney, colon). However, the most abundant source of this enzyme is human placenta, notably placental trophoblast where it is thought to protect the fetus from maternal hypercortisolaemia and play a role in fetal growth and development. During gestation placental trophoblast is exposed to varying oxygen tensions ranging from ~2% - 12%, before and after remodelling of the maternal arteries respectively. Reduced oxygen tension favours trophoblast proliferation rather than differentiation into an invasive phenotype.

11 beta-HSD2 activity studies performed on primary cytotrophoblast cultures prepared from term human placentae (N=3 in triplicate) revealed that 11 beta-HSD2 activity was greatly increased when oxygen tension was reduced from atmospheric levels (20 %). For example at 2% and 8 % oxygen 11 beta-HSD2 activity was significantly elevated to 77.5 +/-4.5 (mean +/- SE) pmoleE\/mg protein\\\/hour (P=<0.01) and 60.2 +/-2.7 P=<0.05, respectively compared to 20% oxygen (48.9 +/-2.9). Increased 11 beta-HSD2 activity as a response to reduced oxygen was also observed in JEG-3 choriocarcinoma cells (N=4 in triplicate); 8.4 +/-0.9 (P=<0.05) and 11.4 +/-0.6 (P=<0.01) at 2% and 8% oxygen, respectively compared to 20% (6.5 +/-1.2). Primary cytotrophoblast also exhibited elevated 11 beta-HSD2 mRNA expression, as a result of reduced oxygen tension. Quantitative real-time PCR analysis showed that, compared to expression at 20% oxygen, 11 beta-HSD2 mRNA levels increased 1.73-fold +\/-0.11 P=<0.01 at 2% oxygen 1.38-fold +/-0.15 P=<0.05 at 8% oxygen.

Given that cortisol is known to have anti-proliferative effects, further study will reveal to what extent 11 beta-HSD2 is involved in mediating the effects of oxygen tension on trophoblast proliferation and differentiation.

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