Adrenomedullin improves fertility and promotes pinopodes and cell junctions in the peri-implantation endometrium

• Published in: Biology of reproduction 2017-09, Vol.97 (3), p.466-477
• Main Authors: Matson, Brooke C, Pierce, Stephanie L, Espenschied, Scott T, Holle, Eric, Sweatt, Imani H, Davis, Eric S, Tarran, Robert, Young, Steven L, Kohout, Trudy A, Duin, Marcel van, Caron, Kathleen M
• Format: Article
• Language: English
• Subjects: Adrenomedullin; Adrenomedullin - pharmacology; Animal models; Animals; assisted reproductive technology; Cell Communication - drug effects; Cell junctions; Connexin 43; Connexin 43 - biosynthesis; Decidua; Decidua - cytology; Decidua - drug effects; Embryo Implantation - drug effects; Embryo Transfer; Endometrium; Endometrium - cytology; Endometrium - drug effects; Epithelium; Female; Fertility; Fertility - drug effects; Fertility Agents, Female - pharmacology; Fetuses; Gap Junctions - drug effects; Haploinsufficiency; Humans; Implantation; In vitro fertilization; in vitro fertilization (IVF); Infertility; Intercellular Junctions - drug effects; mechanisms of hormone action; Mice; Mice, Knockout; Phenotypes; PREGNANCY; Pregnancy complications; Stroma; Uterus; Uterus - cytology; Uterus - drug effects; Water - metabolism
• ISSN: 0006-3363; 1529-7268
• DOI: 10.1093/biolre/iox101

Implantation is a complex event demanding contributions from both embryo and endometrium. Despite advances in assisted reproduction, endometrial receptivity defects persist as a barrier to successful implantation in women with infertility. We previously demonstrated that maternal haploinsufficiency for the endocrine peptide adrenomedullin (AM) in mice confers a subfertility phenotype characterized by defective uterine receptivity and sparse epithelial pinopode coverage. The strong link between AM and implantation suggested the compelling hypothesis that administration of AM prior to implantation may improve fertility, protect against pregnancy complications, and ultimately lead to better maternal and fetal outcomes. Here, we demonstrate that intrauterine delivery of AM prior to blastocyst transfer improves the embryo implantation rate and spacing within the uterus. We then use genetic decrease-of-function and pharmacologic gain-of-function mouse models to identify potential mechanisms by which AM confers enhanced implantation success. In epithelium, we find that AM accelerates the kinetics of pinopode formation and water transport and that, in stroma, AM promotes connexin 43 expression, gap junction communication, and barrier integrity of the primary decidual zone. Ultimately, our findings advance our understanding of the contributions of AM to uterine receptivity and suggest potential broad use for AM as therapy to encourage healthy embryo implantation, for example, in combination with in vitro fertilization. Summary Sentence Intrauterine administration of the endocrine peptide adrenomedullin promotes pinopode formation and cell junctions in the peri-implantation endometrium, bolstering fertility after blastocyst transfer in mice.