Specific inhibition of placental 11β-HSD2 activity also leads to
PE-like features in pregnant rats
As mentioned, the placenta-targeted drug delivery system has just
recently been developed in pregnant mice
(Zhang et al., 2018). To explore whether
this system works in rats, the targets of placenta-targeted
nanoparticles in the pregnant rats were examined. At 48h after
administration of ICG-CSA-NPs, ICG signals were mainly accumulated in
the placenta (supplemental Fig S3). In contrast, very few ICG signals
were found in the placentas of the rats with administration of ICG-NPs.
Moreover, ICG fluorescence was localized in labyrinth zone of the
placentas in the group of ICG-CSA-NPs. These data suggest that this
system also specifically target to the labyrinth zone of placenta in
rats.
Then, we studied the effects of administrating this system loaded with
CBX (0.6mg/kg) on pregnant outcome. We found that specific delivery of
CBX to placenta, ie, administration of CBX-CSA, could also lead to a
significant decrease in 11β-HSD2 expression and activity (Fig.2A) whilst
had no impact on 11β-HSD1 expression level (supplemental Fig.S4).
Administration of CBX-NPs and CBX-NPs-linked to scramble peptide (ie,
CBX-SCR) did not affect 11β-HSD1 and 11β-HSD2 expression
(Fig.2A&supplemental Fig.S4). The levels of corticosterone in placentas
were significantly increased in CBX-CSA group whereas they were not
significantly changed in CBX, CBX-NPs and CBX-SCR groups compared with
vehicle (Fig.2B). Maternal circulatory levels of corticosterone were
significantly elevated in CBX-CSA group from GD 15.5 compared with
vehicle group (Fig.2C). PE-like features also occurred in CBX-CSA group.
As shown in Fig.2D&E, MAP was significantly elevated from GD15.5, and
consistently, SBP measured on GD 20.5 was also elevated. These rats
showed an increase in urine protein/creatinine (Fig.2F) and abnormal
morphology in glomeruli (Fig.2G&H). Administration of CBX-CSA also
suppressed fetal growth as evidenced by a significant decrease in fetal
weight (Fig.2I) and led to a significant increase in sFlt1 level and
sFlt1/PlGF in maternal circulation (Fig.2J), but did not affect
circulatory PlGF and VEGF levels (supplemental Fig.S5). The rats of
CBX-NPs and CBX-SCR groups did not display abnormal BP and renal
morphology as well as abnormal sFlt level and sFlt1/PlGF in maternal
circulation.