Adrenomedullin and pregnancy: perspectives from animal models to humans

Lenhart, Patricia M.; Caron, Kathleen M.

doi:10.1016/j.tem.2012.02.007

Cited by 43 publications

(45 citation statements)

References 99 publications

(101 reference statements)

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“…While there has been general concordance among studies that AM is elevated during a normal pregnancy, but blunted in preeclampsia, there has also been significant variation among studies, due to the inherently poor stability of AM peptide and differences in assays used (reviewed in ref. 23). However, measurement of the highly stable peptide hormone precursor of AM, midregional proadrenomedullin (MR-proAM), can now be performed with such a high level of accuracy that it is showing great clinical value in the context of predicting poor outcomes after myocardial infarction, sepsis, and community-acquired pneumonia (56).…”

Section: Discussionmentioning

confidence: 99%

“…Adrenomedullin (Adm; encoding AM) is a hypoxia-induced, angiogenic peptide vasodilator that is elevated approximately 5-fold in the maternal plasma of normal human pregnancies, but often blunted in pregnancies complicated by preeclampsia (23). Moreover, the direct transcriptional induction of Adm gene expression (and that of its receptor components) by estrogen confers high levels of this peptide signaling pathway in female reproductive organs, including the ovaries, uterus, uterine arteries, and placenta (24)(25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

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Fetal-derived adrenomedullin mediates the innate immune milieu of the placenta

Li¹,

Schwerbrock²,

Lenhart³

et al. 2013

J. Clin. Invest.

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The remodeling of maternal uterine spiral arteries (SAs) is an essential process for ensuring low-resistance, high-capacitance blood flow to the growing fetus. Failure of SAs to remodel is causally associated with preeclampsia, a common and life-threatening complication of pregnancy that is harmful to both mother and fetus. Here, using both loss-of-function and gain-of-function genetic mouse models, we show that expression of the pregnancy-related peptide adrenomedullin (AM) by fetal trophoblast cells is necessary and sufficient to promote appropriate recruitment and activation of maternal uterine NK (uNK) cells to the placenta and ultimately facilitate remodeling of maternal SAs. Placentas that lacked either AM or its receptor exhibited reduced fetal vessel branching in the labyrinth, failed SA remodeling and reendothelialization, and markedly reduced numbers of maternal uNK cells. In contrast, overexpression of AM caused a reversal of these phenotypes with a concomitant increase in uNK cell content in vivo. Moreover, AM dose-dependently stimulated the secretion of numerous chemokines, cytokines, and MMPs from uNK cells, which in turn induced VSMC apoptosis. These data identify an essential function for fetal-derived factors in the maternal vascular adaptation to pregnancy and underscore the importance of exploring AM as a biomarker and therapeutic agent for preeclampsia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fetal-derived adrenomedullin mediates the innate immune milieu of the placenta

Li¹,

Schwerbrock²,

Lenhart³

et al. 2013

J. Clin. Invest.

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“…Therefore, the preeclampsia-like phenotypes of Adm 2/2 placentas recapitulate prior evidence of dysregulation of AM levels in complications of pregnancy. 33 Because uNK cells are the largest population of deciduaspecific immune cells and are established effectors of spiral artery remodeling, uNK cells were counted in Adm 2/2 mouse placentas and found to be fewer in number compared to wildtype placentas. 28 This reduction in uNK cell content was not associated with apopotosis but rather with under-recruitment of uNK cells to the decidua.…”

Section: Maternal-derived Am Is Necessary For Successful Implantationmentioning

confidence: 99%

Adrenomedullin and endocrine control of immune cells during pregnancy

Matson

Caron

2014

Cell Mol Immunol

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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

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“…While the ligands for these receptors are unknown, they are clearly playing an important role in uNK cell maturation and activity, highlighting the importance of interactions outside the KIR-HLA axis. Levels of AM, an anti-inflammatory vasodilator, are physiologically elevated in normal pregnancy (Gibbons et al, 2007) but altered in adverse pregnancy outcomes (Lenhart and Caron, 2012). Polymorphisms in the AM gene are associated with birth weight, glycemic regulation, and preeclampsia .…”

Section: Direct Interactions Between Unk and Trophoblast Cells: Kirs mentioning

confidence: 99%

Uterine natural killer cells as modulators of the maternal-fetal vasculature

Matson¹,

Caron²

2014

Int. J. Dev. Biol.

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Precise and local control of the innate immune system within the placenta is an essential component for achieving a normal and healthy pregnancy. One of the most abundant immune cells of the placenta is a subpopulation of natural killer (NK) cells that profusely populates the uterine decidua during early pregnancy. Uterine NK (uNK) cells and trophoblast cells of the placenta communicate both directly and indirectly to contribute to the critical process of spiral artery remodeling. Here, we discuss recent findings that expand our knowledge of uNK cell-trophoblast cell crosstalk and the important role it plays in the maternal vascular adaptation to pregnancy.

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Adrenomedullin and pregnancy: perspectives from animal models to humans

Cited by 43 publications

References 99 publications

Fetal-derived adrenomedullin mediates the innate immune milieu of the placenta

Fetal-derived adrenomedullin mediates the innate immune milieu of the placenta

Adrenomedullin and endocrine control of immune cells during pregnancy

Uterine natural killer cells as modulators of the maternal-fetal vasculature

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