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

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 (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 11 beta-hydroxysteroid dehydrogenase 2 (11 beta-HSD) in normal pregnancies and in PE. Two types of 11 beta-HSD exist in the placenta, 11 beta-HSD1 and 11 beta-HSD2. 11 beta-HSD2 is thought to protect the fetus from cortisol excess. In PE, both the expression and activity of PL 11 beta-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 11 beta-HSD2 expression changes at the time of the increase in O(2). 11 beta-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 11 beta-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 11 beta-HSD1 expression was observed in early pregnancy or in PE. This is the first report to suggest that 11 beta-HSD2 is O(2) dependent in first and third trimester placenta during human gestation.

The Effects of Glucocorticoids on Fetal and Placental Development

“…11 -HSD2 is better suitable for this role because of its location (the site of maternal-fetal exchange) and its enzymatic properties (higher affinity for cortisol). This enzyme acts as a 'barrier' to prevent premature or inappropriate action at glucocorticoid-responsive tissues during fetal development [44]. It has been suggested that a reduction in the expression or activity of placental 11 -HSD2, by leading to increased transplacental passage of active glucocorticoids, reduces fetal growth.…”

The Acute Autonomic Stress Response and Amniotic Fluid Glucocorticoids in Second-Trimester Pregnant Women

“…It is more likely that LF and LF/HF mirror the activity of other ANS variables known to impair the actions of the placental barrier enzyme, such as NE and EPI (24) or placental oxygen transfer (14). However, future studies need to investigate this hypothesis in more detail.…”

“…In addition, chronic ANS activation may alter 11A-HSD2 activity by reduced placental oxygen transfer. Reduced oxygen seems to impair 11A-HSD2 (14). Correspondingly, prenatal anxiety (55) and psychological distress (56) have been associated with impaired placental blood flow, which, in turn results in reduced placental oxygen supplies (14).…”

“…In rats, acute maternal stress induces an immediate up-regulation of placental 11A-HSD2 activity, but after maternal chronic stress exposure, this up-regulation is impaired resulting in F excess to the fetus (12,13). A parallel process has been proposed to exist in humans because, from 5 weeks of gestation onward, 11A-HSD2 is also present in the human placental syncytiotrophoblast, the site of maternal-fetal exchange (14). Support for this hypothesis comes from a recent study revealing a negative association between anxiety in pregnant women and 11A-HSD2 activity and messenger RNA (mRNA) expression in placental samples obtained directly after birth (15).…”

Spontaneous Miscarriages Are Explained by the Stress/Glucocorticoid/Lipoxin A4 Axis

“…In the placenta, 11b-HSD2 represents the active component of the functional placental barrier that controls the trans-placental passage of germinal centers protecting the fetus against excessive exposure (36,37). The reduced amount and/or activity of 11b-HSD2 in placentas, and the accompanying increase in exposure of the placenta and embryo/fetus to active germinal centers, could be a consequence of impaired placental perfusion and hypoxia (38,39). This study, respectively, used LPS, VSV, and CoCl 2 to construct a mouse model of miscarriage.…”