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Pregnancy |
Department of Obstetrics and Gynecology,3 University of Texas Medical Branch, Galveston, Texas 77555
Regional Bone Center,4 Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903
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 Gestational Day 8 were implanted s.c. with osmotic minipumps delivering 125 and 250 µg rat–1 day–1 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 group receiving 250 µg rat–1 day–1. In these animals, fetal resorption sites were also increased. Apoptosis was demonstrated in placenta and uterus by the 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, levels of active caspase-9 and -3 as well as of Poly ADP ribose polymerase were significantly increased, whereas levels of Bcl-2 protein decreased, compared with controls. However, no significant treatment-associated changes were observed in Bid, Fas, Fas ligand, p53, and 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 on AM22–52 treatment. Conversely, in the cytosol, Bax levels decreased with increases in cytochrome c, demonstrating translocation of Bax from cytosol to mitochondria and 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 mitochondrial apoptotic pathways.
2 Correspondence: Chandrasekhar Yallampalli, Department of Obstetrics & Gynecology, 301 University Blvd., MRB, Rm. 11.138, Galveston, TX 77555-1062. FAX: 409 747 0475; chyallam{at}utmb.edu
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