Fetal-derived adrenomedullin mediates the innate immune milieu of the placenta
Manyu Li, … , Christopher P. Mack, Kathleen M. Caron
Manyu Li, … , Christopher P. Mack, Kathleen M. Caron
Published May 1, 2013
Citation Information: J Clin Invest. 2013;123(6):2408-2420. https://doi.org/10.1172/JCI67039.
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Research Article Reproductive biology Article has an altmetric score of 27

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

Manyu Li, Nicole M.J. Schwerbrock, Patricia M. Lenhart, Kimberly L. Fritz-Six, Mahita Kadmiel, Kathleen S. Christine, Daniel M. Kraus, Scott T. Espenschied, Helen H. Willcockson, Christopher P. Mack, Kathleen M. Caron

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Figure 5

Fetal loss of Calcrl recapitulates Adm–/– placental phenotypes.

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Fetal loss of Calcrl recapitulates Adm–/– placental phenotypes. (A) In...
(A) In situ hybridization of Calcrl gene expression in WT E9.5 mouse placentas revealed expression in parietal TGCs, similar to the pattern of Adm expression. Unlike Adm, Calcrl was expressed at moderate levels in the embryo and fetal membranes. There was also robust expression of Calcrl in cord-like structures throughout the early decidua. (B) Digital zoom of boxed region in A (enlarged ×2-fold), showing punctuate Calcrl staining in TGCs lining the ectoplacental cone at the innermost border of the maternal-fetal interface and little to no expression in the chorionic plate. (C) Calcrl expression was diffuse throughout the labyrinth at E13.5 and robustly expressed in the maternal endothelial cells lining the decidual SAs (arrows, inset; enlarged ×2-fold). (D) H&E staining of placentas from Calcrl+/+ and Calcrl–/– littermates revealed largely normal structures, with no appreciable differences in layers. Digital zoom of central part of placentas is shown at the right of each image (enlarged ×1.5-fold). (E–H) Calcrl–/– placentas at E13.5 displayed the same pathological phenotypes of Adm–/– placentas — including (E) reduced fetal vessel branching in the labyrinth, as visualized by isolectin staining, (F) retention of SMCs around maternal SAs, and (G and H) significantly reduced number of DBA+ uNK cells — compared with Calcrl+/+ littermate placentas. *P < 0.001. n ≥ 6 placentas analyzed per genotype. Data are mean ± SEM. Original magnification, ×4 (A–C). Scale bars: 1 mm (D); 50 μM (E and G); 10 μM (F).