Introduction
Preeclampsia (PE) is a major human pregnancy-specific disorder that
leads to maternal and fetal morbidity and mortality
(Roberts & Cooper, 2001;
Sibai et.al., 2005). The pathogenesis of
PE remains largely unknown, however, it is widely accepted that PE is
initiated by shallow invasion of trophoblasts into the uterine wall and
thereafter results in abnormal placentation followed by increased
release of placenta-produced factors into the maternal
circulation(Seki, 2014;
Szpera-Gozdziewicz & Breborowicz, 2014).
These in turn cause dysfunction of the maternal endothelium, leading to
the preeclamptic clinical symptoms. In the past decades, many efforts
have therefore been made to uncover the critical factors relevant to
placenta development and pathogenesis of PE in placenta.
Glucocorticoids (GCs) are involved in many events during pregnancy
including embryo implantation, growth and development of the fetus and
placenta as well as initiation of parturition
(Fowden & Forhead, 2015;
Zannas & Chrousos, 2015). The
gestational tissues including placentas, fetal membranes and deciduas
are the targets of GCs. Interestingly, most of target tissues of GCs
usually express 11β-hydroxysteroid dehydrogenase (11β-HSD) which
catalyzes the rapid metabolism of cortisol (corticosterone in rodents)
to inert 11-keto derivatives (cortisone, 11-dehydrocorticosterone),
thereby controlling local availability of active GCs
(Hunter & Bailey, 2015). This enzyme
exists as, at least, two isoforms; 11β-HSD1 (which is bidirectional but
favors reduction of inactive cortisone to active cortisol) and 11β-HSD2
(which operates essentially as a unidirectional dehydrogenase,
converting cortisol to cortisone)(Burton &
Waddell, 1999; Hunter & Bailey, 2015;
Patel et al., 1999). In placenta, both of
11β-HSD1 and 2 have been identified, however, 11β-HSD2 is predominant
(Brown et al., 1996;
Burton & Waddell, 1999;
Patel et al., 1999).
Thus,
11β-HSD2 maintains a concentration gradient of active GC levels between
the mother’s and the fetus’s compartments and constitutes a specific
barrier protecting the fetus from the maternal GCs. Placental 11β-HSD2
expression and activity are found to be significantly downregulated in
PE patients, which is associated with higher GC level in placentas of
these patients(Alfaidy et al., 2002;
Brown et al., 1996;
Causevic & Mohaupt, 2007; He et al.,
2014; Schoof et al., 2001). As GCs have a
detrimental proapoptotic effect when they are in excess, downregulated
11β-HSD2 in placenta is implicated to be associated with intrauterine
growth retardation (IUGR) in PE patients
(Causevic & Mohaupt, 2007; Hofmann et al,
2001). To our knowledge, whether 11β-HSD2 dysfunction is involved in the
pathogenesis of PE has not been reported. Of note, recent studies have
shown that synthetic GCs can modulate placental trophoblast function
including invasion and proliferation in vitr o
(Kisanga et al., 2018;
Mandl et al.,2006; Pavek et al., 2007).
Thus, it would be of great interest to explore the effects of excessive
GCs caused by placental 11β-HSD2 downregulation on pregnant outcome.
The objectives of the present study were to explore the potential role
of placental 11β-HSD2 in the pathogenesis of PE and underlying
mechanisms using animal and human models. Given that carbenoxolone (CBX)
has been proven to be able to inhibit 11β-HSD2 activity both in
vitro and in vivo (Duax et al.,
2000; Lindsay et al., 1996;
Sanna et al., 2016;
Stewart, et al.,1990), we firstly
investigated the effects of subcutaneous administration of CBX on the
pregnant outcome in pregnant rats. Since a drug delivery system of
placenta-targeted nanoparticles has recently been developed
(Zhang et al., 2018), we then examined
the effects of specific delivering CBX to placenta on pregnant outcome
in rats in order to eliminate the potential effect of CBX on other
organs which might affect the outcomes. Furthermore, we elucidated the
potential mechanisms underlying 11β-HSD2 linked to PE pathogenesis using
animal models and in vitro human tissue and cell models. Here, we
revealed an important role of 11β-HSD2 in placental development and
balance release of pro- and anti-angiogenic factors in placenta and
immediately identified a novel target for therapeutic management of PE
development.