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Localization and Developmental Regulation of 11ß-Hydroxysteroid Dehydrogenase-1 and -2 in the Baboon Syncytiotrophoblast¹

Department of Physiological Sciences, Eastern Virginia Medical School (G.J.P., M.G.B.), Norfolk, Virginia 23507; and Departments of Obstetrics/Gynecology/Reproductive Sciences and Physiology, Center for Studies in Reproduction, University of Maryland School of Medicine (E.D.A.), Baltimore, Maryland 21201

Address all correspondence and requests for reprints to: Gerald J. Pepe, Ph.D., Department of Physiological Sciences, Eastern Virginia Medical School, P.O. Box 1980, Norfolk, Virginia 23501-1980. E-mail: pepegj{at}evms.edu

We previously showed that the messenger RNA and protein levels of the 11ß-hydroxysteroid dehydrogenase (11ßHSD) enzymes catalyzing glucocorticoid reduction (11ßHSD-1) and oxidation (11ßHSD-2) increased with advancing baboon gestation and concluded that the estrogen-regulated change in placental cortisol metabolism from reduction at midgestation to oxidation near term is not simply the result of a change in the relative concentrations of these two enzymes. Therefore, in the current study we determined whether 11ßHSD-1 and -2 are located in different regions of the baboon and human syncytiotrophoblast and whether there is a developmental change in their localization with advancing baboon gestation. Western blot analyses, immunofluorescence, and electron microscopic immunocytochemistry indicated that 11ßHSD-1 expression was abundant in microvillus membranes (MVM) juxta the maternal circulation, and their levels are significantly lower, but detectable, in more internal regions of the syncytiotrophoblast, including membranes contiguous with the basal membrane (BM_m) facing the fetal vasculature in both the human and baboon. In contrast, in both species 11ßHSD-2 expression was limited in the MVM and extensive throughout the remainder of the syncytiotrophoblast, including the BM_m. In the baboon, the relative mean (±SE) concentrations (arbitrary densitometric units per µg protein) of 11ßHSD-1 in the MVM were similar at mid (i.e. day 100; 38,859 ± 3,484; n = 3) and late (i.e. day 180; 43,561 ± 1,784; n = 3) gestation (term = day 184) and exceeded (P < 0.01) respective values for 11ßHSD-2 by approximately 16-fold. In contrast, levels of 11ßHSD-1 in the BM_m declined (P < 0.05) by approximately 50% between mid (7,099 ± 758) and late (4,013 ± 738) gestation, whereas levels of 11ßHSD-2 in this fraction increased. Thus, the ratio of 11ßHSD-2 to 11ßHSD-1 in the BM_m at midgestation (1.22 ± 0.10) was increased (P < 0.05) 2-fold in late gestation (2.66 ± 0.05). Collectively, these findings indicate that the 11ßHSD-1 and -2 enzymes are localized to different membrane fractions of the baboon and human placental syncytiotrophoblast. Moreover, we propose that the developmental increase in the ratio of 11ßHSD-2 to 11ßHSD-1 in membranes facing fetal blood near term is consistent with and perhaps the subcellular mechanism responsible for the previously demonstrated switch in transplacental glucocorticoid metabolism from reduction at midgestation to oxidation late in gestation and appears to be responsible for the activation/maturation of the fetal pituitary-adrenocortical axis.

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