title: Fetal-derived adrenomedullin mediates the innate immune milieu of the placenta.
abstract: 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.
authors: Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors: Manyu
authors: M
authors: Li
authors: Nicole M J
authors: NM
authors: Schwerbrock
authors: Patricia M
authors: PM
authors: Lenhart
authors: Kimberly L
authors: KL
authors: Fritz-Six
authors: Mahita
authors: M
authors: Kadmiel
authors: Kathleen S
authors: KS
authors: Christine
authors: Daniel M
authors: DM
authors: Kraus
authors: Scott T
authors: ST
authors: Espenschied
authors: Helen H
authors: HH
authors: Willcockson
authors: Christopher P
authors: CP
authors: Mack
authors: Kathleen M
authors: KM
authors: Caron
mesh_terms: D053607:Adrenomedullin / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D058286:Calcitonin Receptor-Like Protein / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D003656:Decidua / Q000276:immunology / Q000473:pathology; D005260:Female; D005333:Fetus / Q000276:immunology / Q000378:metabolism*; D015726:Giant Cells / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008297:Male; D008431:Maternal-Fetal Exchange / Q000276:immunology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D010641:Phenotype; D010920:Placenta / Q000098:blood supply / Q000276:immunology* / Q000378:metabolism; D011225:Pre-Eclampsia / Q000276:immunology; D011247:Pregnancy; D058265:Receptors, Adrenomedullin / Q000378:metabolism; D014327:Trophoblasts / Q000473:pathology
chemical_list: D058286:Calcitonin Receptor-Like Protein; C545579:Calcrl protein, mouse; D018925:Chemokines; D058265:Receptors, Adrenomedullin; D053607:Adrenomedullin; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
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