Adrenomedullin2 (ADM2)/Intermedin (IMD) in Rat Ovary: Changes in Estrous Cycle and Pregnancy and Its Role in Ovulation and Steroidogenesis1

Abstract

Adrenomedullin2 (ADM2) is reported to facilitate embryo implantation and placental development. Therefore, the current study was undertaken to identify if ADM2 has a functional role in ovary to facilitate its reproductive actions. This study shows that the expression of ADM2 is differentially regulated in rat estrous cycle and that ADM2 increases the synthesis and secretion of 17beta-estradiol accompanied with an increase in the expression of steroidogenic factor 1 (Sf1), estrogen receptor Esr1, and enzymes involved in steroidogenesis in equine chorionic gonadotropin (eCG)-treated rat ovaries. In addition, inhibition of endogenous ADM2 function in eCG-treated immature rats caused impaired ovulation. Furthermore, the mRNA expression of Adm2 and receptor activity modifying protein 3 is higher in the ovary on Day 18 compared to nonpregnant and pregnant rats on Day 22. ADM2-like immunoreactivity is localized in granulosa cells, blood vessels, oocytes, cumulous oophorus, and corpus luteum of pregnant ovaries, suggesting a potential role for ADM2 in the ovary. This is supported by the presence of ADM2-like immunoreactivity in the corpus luteum during pregnancy and a decline in aromatase immunoreactivity in corpus luteum on Day 9 of gestation in rats infused with ADM2 antagonist during implantation and decidualization phase. Taken together, this study suggests a potential involvement of ADM2 in the rat ovary in regulating synthesis of estradiol to support ovulation and facilitate efficient implantation and placental development for a successful pregnancy.

Oocyte-specific disruption of adrenomedullin 2 gene enhances ovarian follicle growth after superovulation

“…In addition, we found that fertilized eggs from homozygous mice exhibit impaired developmental capacity in vitro . Although earlier studies have shown that ADM2 facilitates follicle growth and COC formation in vitro ( 38 , 39 , 61 ), the present study actually found that oocyte-specific Adm2 disruption enhances the ovulation rate after gonadotropin treatment. These results suggested the oocyte-derived ADM2 plays a more complex role in folliculogenesis and may act to limit the number of growing follicles that can reach maturity after a gonadotropin surge in vivo independent of the closely related ADM and CGRPs.…”

“…In addition, we found that fertilized eggs from homozygous mice exhibit impaired developmental capacity in vitro. Although earlier studies have shown that ADM2 facilitates follicle growth and COC formation in vitro (38,39,61), the present study actually found that oocyte-specific…”

“…Importantly, Adm2 is also highly expressed in oocytes ( 1 , 36 ), and we have shown that ADM2 is important for maintaining the integrity of cumulus-oocyte complex (COC) in vitro and normal cyclin D2 expression in follicles ( 38 ). Consistent with these observations, blockage of ADM2 signaling impaired follicle growth in vitro and ovulation in gonadotropin-primed rats, perhaps due to the inhibition of estradiol-mediated signaling pathways ( 39 , 61 ). Despite these observations, whether oocyte-derived ADM2 is essential for normal folliculogenesis physiologically remains to be determined.…”

“…In the ovary, ADM and CGRPs are mainly expressed in growing follicles and corpora lutea, and nerve endings, respectively ( 1 , 56 – 60 ). Like ADM, ADM2 expression is localized in granulosa cells, blood vessels, cumulous oophorus, and corpus luteum ( 38 , 61 ). Importantly, Adm2 is also highly expressed in oocytes ( 1 , 36 ), and we have shown that ADM2 is important for maintaining the integrity of cumulus-oocyte complex (COC) in vitro and normal cyclin D2 expression in follicles ( 38 ).…”

Intermedin 1-53 Inhibits Myocardial Fibrosis in Rats by Down-Regulating Transforming Growth Factor-β

“…It is expressed in tissues and organs such as human cardiac cells, coronary arterial smooth muscle cells, and hypothalamic supraoptic nucleus [3,5–9], which indicates that IMD may be involved in regulating the environmental homeostasis of the body.…”