Adrenomedullin and endocrine control of immune cells during pregnancy

Abstract

The immunology of pregnancy is complex and incompletely understood. Aberrant immune activity in the decidua and in the placenta is believed to play a role in diseases of pregnancy, such as infertility, miscarriage, fetal growth restriction and preeclampsia. Here, we briefly review the endocrine control of uterine natural killer cell populations and their functions by the peptide hormone adrenomedullin. Studies in genetic animal models have revealed the critical importance of adrenomedullin dosage at the maternal-fetal interface, with cells from both the maternal and fetal compartments contributing to essential aspects underlying appropriate uterine receptivity, implantation and vascular remodeling of spiral arteries. These basic insights into the crosstalk between the endocrine and immune systems within the maternalfetal interface may ultimately translate to a better understanding of the functions and consequences of dysregulated adrenomedullin levels in clinically complicated pregnancies. Keywords: adrenomedullin; preeclampsia; pregnancy; spiral artery remodeling; uNK cells INTRODUCTION Pregnancy presents a mysterious immunological paradox that is permitted by the complex, unique immunology of the maternalfetal interface. We are only beginning to understand how this very specialized immune 'subsystem' differs from the systemic immune system and thus effectively protects the fetus from maternal rejection. For example, the sizable uterine natural killer (uNK) cell and macrophage populations found during early pregnancy are distinctive in their cell surface markers and functions compared to their peripheral counterparts. 1,2 Understanding the activity and control of these immune cell types will shed light on this immunological paradox and possibly inform the pathophysiology of complications of pregnancy.During the past decade, numerous studies have characterized critical roles for the peptide hormone adrenomedullin (Adm gene; AM protein) in the establishment and maintenance of a healthy pregnancy. Here, we discuss the effects of AM on implantation and placentation, concentrating on the control of the uNK cell population and its subsequent involvement in the process of spiral artery remodeling-a necessary process for the maternal vascular adaptation to pregnancy. Importantly, studies addressing the link between

Hyperoxia exposure disrupts adrenomedullin signaling in newborn mice: Implications for lung development in premature infants

“…Recently, AM signaling is increasingly been recognized as a necessary pathway for vascular remodeling and immune response in physiological states such as pregnancy [23], and disrupted AM signaling is shown to contribute to several pathophysiological states such as preeclampsia [24], systemic and pulmonary hypertension [25, 26], myocardial infarction [27], tumors [28], and lymphedema [29]. Further, Calcrl-RAMP complexes are being explored as important drug targets to treat acute myocardial infarction, pulmonary hypertension, migraine headache, cancer, and several other disorders [30–32], indicating that AM signaling axis can be targeted to develop therapies.…”

Decidual natural killer cells and the immune microenvironment at the maternal-fetal interface

“…During early embryonic development, blastocyst adhesion and endometrial implantation is accompanied by endometrial cells forming decidual stromal cells (DSCs) as promoted by estrogen and progesterone (Matson and Caron, 2014). In the microenvironment created by DSCs, blastocysts differentiated into functionally unique villous trophoblast cells (EVTs).…”

Trophoblast VIP deficiency entails immune homeostasis loss and adverse pregnancy outcome in mice

“…ABBREVIATIONS: EIA, enzyme immunoassay; EPC, ectoplacental cone; H&E, hematoxylin and eosin; KO, knockout; LCM, laser capture microdissection; MMP, matrix metalloproteinase; sENG, soluble endoglin; TGC, trophoblast giant cell; T reg , regulatory T; VIP, vasoactive intestinal peptide; WT, wild type Multiple hormonal and peptidic regulatory factors are known to regulate trophoblast-cell invasiveness and their interaction with maternal immune cells (17)(18)(19)(20). The vasoactive intestinal peptide (VIP) is a 28 aa neuropeptide with vasodilating, prosecretory, and CNS modulatory effects (21)(22)(23).…”