Molecular Regulators of Embryo Implantation and Pregnancy

Embryo implantation is one of the first steps in the establishment of pregnancy and sets the stage for proper embryonic and placental development. We are beginning to appreciate the complexity of implantation and its demand for synchrony between embryo and endometrium. Over the years, many groups have identified and studied both embryonic and endometrial factors affecting implantation, but there is still much to learn. Here, we focus on the endocrine peptide adrenomedullin (Adm, AM) and its association with female reproductive physiology and disease in both mice and humans. In Part I, we elaborate on the subfertility phenotype of Adm heterozygous female mice by testing whether AM supplementation before implantation can improve fertility and pregnancy outcomes. We find that administration of AM directly to the mouse uterus before blastocyst transfer enhances implantation success and inter-embryonic spacing. Intra-uterine delivery of AM also confers morphological and cellular changes to the uterine epithelium and stroma that are associated with endometrial receptivity and believed to be beneficial for implantation. We also test mid-regional pro-adrenomedullin (MR-proADM), a stable surrogate for AM peptide, as a biomarker for endometriosis, which is comorbid with infertility. Our studies identify novel mechanisms of action of AM in the endometrium in support of implantation and the establishment of pregnancy, providing a foundational basis for the use of AM as a clinical therapeutic for infertility. In Part II, we address the role of AM in the maintenance of a healthy pregnancy by expanding upon previous studies in mouse models with clinical samples from women with severe preeclampsia, a placental vascular disorder characterized by hypertension and proteinuria. Because Adm-/- placentas exhibit a preeclampsia-like phenotype, we test the hypothesis that MR-proADM concentrations are decreased in plasma from women with severe preeclampsia. Indeed, we find that MR-proADM levels are blunted in women with severe preeclampsia and that MR-proADM is similarly effective as other established biomarkers of preeclampsia at distinguishing between cases and controls. Altogether, our studies in both mice and humans point to diagnostic and therapeutic applications for AM in the context of female reproductive disease.Doctor of Philosoph