INFUSION OF ADRENOMEDULLIN-2 ANTAGONIST INDUCES APOPTOSIS AND CHANGES m-RNA EXPRESSION LEVELS OF ADM2 RECEPTORS IN PLACENTA OF PREGNANT RATS DURING LATE GESTATION AND CAUSES FETOPLACENTAL GROWTH RESTRICTION

Adrenomedullin-2 or Intermedin (ADM2/IMD) is newly identified novel hormone belongs to peptide family like AM, calcitonin, CGRP, amylin and it is widely distributed in various tissues including ovaries, uterus & placenta. The aim of present study was to investigate the role endogenous ADM2 in fetoplacental development in pregnant rats during late gestation period through infusion of ADM2 antagonist. For this study we have infused ADM2 antagonist (ADM2_17-47) at 50 and 200 µg / rat / day exposed continuously by inserting osmotic mini pumps to pregnant wistar rats on gestational day 18 and were sacrificed on gestational day 22.The results showed that infusion of ADM2 antagonist significantly decreases (P<0.05) the total sac weight, fetoplacental weights, length of the fetus and also the serum progesterone & estrogen levels. High molecular DNA fragmentation was observed in ADM2_17-47 treated placental tissues and in immunohistopathological studies apoptotic cells (pyknosis & karyorrhexis cells) and active caspase-3 positive immunoreactivity cells were observed in labyrinth zone of placental tissues. In western blot analysis the levels of caspase-3 was significantly increased in ADM2 _17-47 treated rats than compared to controls. Furthermore, antagonism of ADM2 antagonist significantly decreased (P<0.05) the mRNA expression levels of ADM2 receptors CRLR, RAMP1, and RAMP3 but not in RAMP2. Finally we conclude that ADM2 antagonist acts as a non-competitive inhibitor for endogenous ADM2 and inhabited the actions of ADM2 in fetoplacental development and causes fetal growth restriction.