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Abstract
Adrenomedullin (AM), a potent vasorelaxant peptide, has
been shown to function as an angiogenic and growth factor.
The present study investigated whether antagonism of
endogenous AM in rats during early gestation results in
diminished placental and fetal growth and whether this
occurs through induction of apoptosis. Rats on gestation
day 8 were subcutaneously implanted with osmotic minipumps
delivering 125 and 250 µg per rat per day of
AM22-52 and were killed on gestational day 15.
In AM22-52 treated rats, both placental and
fetal weights were dose-dependently inhibited, with 50%
reduction in the 250 µg per day per rat group. In these
animals, fetal resorption sites were also increased.
Apoptosis was demonstrated in placenta and uterus by the
terminal deoxynucleotidyl transferase deoxy-uridine
triphosphate-nick end labeling (TUNEL) method. Apoptotic
changes were more apparent in trophoblast cells in the
Labyrinth zone of placenta and uterine decidua of
AM22-52-treated rats when compared with vehicle
control rats. Immunoreactivity to active caspase-3 protein
was abundant in the placenta and uterus of the
AM22-52-treated group. Western blot analysis
demonstrated that in homogenates of both the placenta and
uterus of AM22-52-treated rats active caspase-9
and -3, and Poly ADP ribose polymerase (PARP) levels were
significantly increased, while Bcl-2 protein decreased
compared with that in controls. However, no significant
treatment-associated changes were observed in Bid, Fas,
FasL, p53, caspase-8 and -10 proteins in either placenta
or uterus. Bad protein was undetectable in either tissue.
In mitochondrial fractions from both placenta and uterus,
the levels of Bax increased with decreases in cytochrome c
upon AM22-52 treatment. Conversely, in the
cytosol, Bax levels decreased with increases in cytochrome
c demonstrating translocation of Bax from cytosol to
mitochrondria and the release of cytochrome c from
mitochondria with AM22-52 treatment. In
conclusion these findings show that antagonism of AM in
rats during early pregnancy caused fetoplacental growth
restriction through the activation of mitochrondrial
apoptotic pathways.
Key words:
Pregnancy •
Apoptosis •
Placenta
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