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.