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Adrenomedullin antagonist treatment during early gestation in rats causes fetoplacental growth restriction through apoptosis.
Biol Reprod. 2004 Nov; 71(5):1475-83.BR

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 Gestational Day 8 were implanted s.c. with osmotic minipumps delivering 125 and 250 microg rat(-1) day(-1) of AM(22-52) and were killed on Gestational Day 15. In AM(22-52)-treated rats, both placental and fetal weights were dose-dependently inhibited, with 50% reduction in the group receiving 250 microg 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 AM(22-52)-treated rats when compared with vehicle-control rats. Immunoreactivity to active caspase-3 protein was abundant in the placenta and uterus of the AM(22-52)-treated group. Western blot analysis demonstrated that in homogenates of both the placenta and uterus of AM(22-52)-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 AM(22-52) 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 AM(22-52) 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.

Authors+Show Affiliations

Department of Obstetrics and Gynecology, University of Texas Medical Branch, 301 University Blvd., Galveston, Texas 77555, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15229133

Citation

Penchalaneni, Josthna, et al. "Adrenomedullin Antagonist Treatment During Early Gestation in Rats Causes Fetoplacental Growth Restriction Through Apoptosis." Biology of Reproduction, vol. 71, no. 5, 2004, pp. 1475-83.
Penchalaneni J, Wimalawansa SJ, Yallampalli C. Adrenomedullin antagonist treatment during early gestation in rats causes fetoplacental growth restriction through apoptosis. Biol Reprod. 2004;71(5):1475-83.
Penchalaneni, J., Wimalawansa, S. J., & Yallampalli, C. (2004). Adrenomedullin antagonist treatment during early gestation in rats causes fetoplacental growth restriction through apoptosis. Biology of Reproduction, 71(5), 1475-83.
Penchalaneni J, Wimalawansa SJ, Yallampalli C. Adrenomedullin Antagonist Treatment During Early Gestation in Rats Causes Fetoplacental Growth Restriction Through Apoptosis. Biol Reprod. 2004;71(5):1475-83. PubMed PMID: 15229133.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Adrenomedullin antagonist treatment during early gestation in rats causes fetoplacental growth restriction through apoptosis. AU - Penchalaneni,Josthna, AU - Wimalawansa,Sunil J, AU - Yallampalli,Chandrasekhar, Y1 - 2004/06/30/ PY - 2004/7/2/pubmed PY - 2005/2/23/medline PY - 2004/7/2/entrez SP - 1475 EP - 83 JF - Biology of reproduction JO - Biol Reprod VL - 71 IS - 5 N2 - 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 microg rat(-1) day(-1) of AM(22-52) and were killed on Gestational Day 15. In AM(22-52)-treated rats, both placental and fetal weights were dose-dependently inhibited, with 50% reduction in the group receiving 250 microg 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 AM(22-52)-treated rats when compared with vehicle-control rats. Immunoreactivity to active caspase-3 protein was abundant in the placenta and uterus of the AM(22-52)-treated group. Western blot analysis demonstrated that in homogenates of both the placenta and uterus of AM(22-52)-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 AM(22-52) 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 AM(22-52) 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. SN - 0006-3363 UR - https://www.unboundmedicine.com/medline/citation/15229133/Adrenomedullin_antagonist_treatment_during_early_gestation_in_rats_causes_fetoplacental_growth_restriction_through_apoptosis_ L2 - https://academic.oup.com/biolreprod/article-lookup/doi/10.1095/biolreprod.104.032086 DB - PRIME DP - Unbound Medicine ER -