Expression of Adrenomedullin, a Hypotensive Peptide, in the Trophoblast Giant Cells at the Embryo Implantation Site in Mouse

Abstract

Adrenomedullin (AM) is a newly discovered hypotensive peptide which is believed to play an important role for blood pressure control in the adult. Although it has been well established that a major production site of AM is vascular endothelial cells, we now show that AM is most highly expressed in trophoblast giant cells, which are derived from the conceptus and are directly in contact with maternal tissues at the implantation site. Northern blot and in situ hybridization analyses show that the AM mRNA begins to be detected just after implantation and its level peaks at 9.5 days postconception (d.p.c.) in those cells. Expression then falls dramatically after 10.5 d.p.c., coincident with the completion of the mature chorioallantoic placenta. Immunohistochemical analyses show that the AM peptide is secreted from the trophoblast giant cells into the surrounding tissues, i.e., embryo, decidua, and maternal circulation. In contrast, the expression of an AM receptor was not detected by Northern blot analyses in either embryo or trophoblast giant cells at 7 d.p.c., when the AM gene is most highly expressed in the trophoblast giant cells. This suggests that the AM produced and secreted from the embryo's trophoblast giant cells acts on the maternal tissues rather than on the embryonic tissues. Based on these results, we propose that the high production of AM may be the mechanism by which the embryos survive at the early postimplantation period by pooling maternal blood in the implantation site in order to secure nutrition and oxygen before the establishment of efficient embryo-maternal circulation through the mature placenta.

Proadrenomedullin NH2-terminal 20 peptide (PAMP) and adrenomedullin bind to teratocarcinoma cells☆

“…In extraembryonic structures such as giant trophoblastic cells, high levels of ADM and PAMP are expressed [22]. High expression of ADM in trophoblastic cells at the implantation site has been reported [42]. Because ADM and PAMP are differentially expressed during development, they may regulate differentiation in a paracrine manner.…”

Adrenomedullin in mammalian embryogenesis

“…Because of the timing of AM expression in these cells (AM mRNA starts to be detected at 6.5 d.p.c., peaks at 9.5 d.p.c., and falls to a much lower levels after 10.5 d.p.c. ), it was proposed that AM may act on the blood vessels by pooling maternal blood in the implantation site, securing nutrition and O 2 at this early postimplantation period when an efficient chorioallantoic placenta is not yet established (Yotsumoto et al, 1998). These authors, however, did not find a detectable expression of the L1 AM receptor in extraembryonic tissues by Northern blot analysis.…”

“…4) . Subsequently, a more detailed study of AM expression at the peri-implantation stage was conducted (Yotsumoto et al, 1998), since AM was found to be one of the genes highly expressed in a cDNA library from the ectoplacental cone of 7 days postconception (d.p.c.) mouse embryos.…”

Adrenomedullin and endocrine control of immune cells during pregnancy

“…17 At the cellular level, many studies have described Adm expression in several tissues derived from both the mother and the fetus: ovary, uterus, placenta and fetal membranes. [18][19][20][21][22][23][24] For example, just prior to implantation in mice, Adm is highly expressed in the trophectoderm cells of the early blastocyst and the luminal epithelial cells of the uterine lining. 20,25,26 Shortly after implantation, and during the rapid expansion of the murine decidua, Adm expression is strongly centered within the primary decidual zone, a 3-5 cell-layer thick region surrounding the recently implanted embryo which serves as a temporary and physical barrier to immunological attack.…”

“…[18][19][20][21][22][23][24] For example, just prior to implantation in mice, Adm is highly expressed in the trophectoderm cells of the early blastocyst and the luminal epithelial cells of the uterine lining. 20,25,26 Shortly after implantation, and during the rapid expansion of the murine decidua, Adm expression is strongly centered within the primary decidual zone, a 3-5 cell-layer thick region surrounding the recently implanted embryo which serves as a temporary and physical barrier to immunological attack. 26 However, Adm expression is most enriched in mouse trophoblast giant cells (TGCs) throughout pregnancy, with approximately 30-fold higher levels in differentiated TGCs compared to undifferentiated precursors.…”