Adrenomedullin 2 antagonist infusion to rats during midgestation causes fetoplacental growth restriction through apoptosis.
Adrenomedullin 2 (ADM2) is a recently discovered member of the calcitonin/calcitonin gene-related peptide family with an exon-intron structure similar to that of ADM. The mRNA of ADM2 is expressed in several tissues, including uterus and ovary. The present study was designed to assess the effects of ADM2 antagonist (ADM2(17-47)) infusion to pregnant rats on fetal and placental growth. On Day 15 of gestation, rats were implanted s.c. with osmotic minipumps delivering 50 and 200 mug per rat per day of ADM2(17-47) and were killed on Gestational Day 18. In ADM2(17-47)-treated rats, placental weights were significantly inhibited in a dose-related manner, with an 11% reduction in the group of rats receiving 200 microg/day, whereas the fetal weights were reduced by 17% without significant differences between the two doses. 2 In ADM2(17-47)-infused rats, increased apoptosis was demonstrated in the labyrinth and junctional zones of rat placenta by the TUNEL method compared with the control animals. Western blot analysis demonstrated that in ADM2(17-47)-treated rats Bcl-2, mitochondrial cytochrome c, and active caspase-9 and caspase-3 were significantly increased compared with the controls. No significant treatment-associated changes were observed in Bax, Bid, p53, and caspase-8 and caspase-10 proteins in the treated placentas. In addition, infusion of ADM2(17-47) caused a significant decline in the transcripts of nitric oxide synthase 3 (NOS3) and NOS2. These findings show that ADM2(17-47) infusion in rats during midpregnancy cause fetoplacental growth restriction through the activation of mitochondrial apoptotic pathways. This study demonstrates for the first time (to our knowledge) a potential role for ADM2 in placental functions during pregnancy.
Chauhan
Madhu
M
Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Yallampalli
Uma
U
Reed
Luckey
L
Yallampalli
Chandrasekhar
C
D053607:Adrenomedullin / Q000037:antagonists & inhibitors*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053455:Caspase 10 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D005317:Fetal Growth Retardation / Q000139:chemically induced* / Q000473:pathology*; D005865:Gestational Age; D020287:In Situ Nick-End Labeling; D008928:Mitochondria / Q000502:physiology; D009479:Neuropeptides / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D010446:Peptide Fragments / Q000494:pharmacology; D036361:Peptide Hormones / Q000494:pharmacology*; D010920:Placenta / Q000473:pathology; D011247:Pregnancy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C499411:Adm2 protein, rat; D009479:Neuropeptides; D010446:Peptide Fragments; D036361:Peptide Hormones; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C561869:intermedin (17-47); D053607:Adrenomedullin; D045304:Cytochromes c; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D053455:Caspase 10; D053148:Caspase 3; D053181:Caspase 8