Adrenomedullin and pregnancy: perspectives from animal models to humans

Abstract

A healthy pregnancy requires strict coordination of genetic, physiologic and environmental factors. The relatively common incidence of infertility and pregnancy complications has resulted in increased interest in understanding the mechanisms that underlie normal versus abnormal pregnancy. The peptide hormone adrenomedullin (AM) has recently been the focus of some exciting breakthroughs in the pregnancy field. Supported by mechanistic studies in genetic animal models, there continues to be a growing body of evidence demonstrating the importance of AM protein levels in a variety of human pregnancy complications. With more extensive mechanistic studies and improved consistency in clinical measurements of AM, there is great potential for the development of AM as a clinically-relevant biomarker in pregnancy and pregnancy complications.

Figure 1. Adrenomedullin expression in multiple stages of pregnancy

A) AM expression is regulated by estrogen (E2), progesterone, and hypoxia inducible factor 1α (HIF-1a). At the pre-implantation stage, AM is expressed by both the trophectoderm cells and the luminal epithelium, promoting uterine receptivity. The maternal components are colored blue and red while the fetal components are depicted in green and gray. B) At the site of implantation, AM continues to be expressed from the trophectoderm cells and from the luminal epithelium, which is important for successful implantation. C) In the developed placenta, AM is most highly expressed by trophoblast giant cells (mice) or extravillous cytotrophoblasts (humans) and may contribute to the maintenance of placental vascular tone. For both B and C, maternal components are colored blue and red and the fetal components are depicted in green and yellow.

Figure 2. Clinically relevant AM polymorphisms

The structure of the adrenomedullin gene and the location of clinically relevant AM polymorphisms are shown. The dark green box represents AM, light green represents proAM, the prohormone for both AM and proadrenomedullin N-terminal 20 peptide (PAMP). and blue represents noncoding regions of the AM gene. Polymorphisms in AM have been associated with changes in plasma AM levels, drug responses, blood pressure, proteinuria, renal disease, dysglycemia, and preeclampsia.