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

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 6

Genetic overexpression of fetal Adm reverses the placental preeclampsia phenotypes and drives uNK recruitment to the decidua.

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Genetic overexpression of fetal Adm reverses the placental preeclampsia ...
(A) Targeting vector for generation of Admhi/hi mice consisted of (a) a 6-kb genomic fragment of the Adm gene isolated from a 129S6/SvEv genomic phage library and containing all 4 exons and 5′UTR and 3′UTR of the Adm gene, (b) the bovine growth hormone polyA sequence (bGH 3′UTR), (c) 2 tandem copies of the 1.2-kb 5′ insulator sequence from chicken β-globin gene (2XIns), (d) 1.3 kb of pMC1 promoter–driven neomycin (Neo), (e) 80 bp of AU/U-rich element of the mouse c-fos gene (ARE), and (f) 2 loxP recombination sites. The latter 5 elements were cloned as a cassette, 23 bp downstream of the endogenous Adm stop codon. (B) Southern blot analysis on genomic DNA confirmed correct targeting of the Admhi allele. (C) Adm gene expression in placentas from Adm+/+ and Admhi/hi mice, analyzed by quantitative RT-PCR, showed a significant 3-fold increase in gene expression level. *P < 0.05. (D–G) Admhi/hi placentas (D) appeared histologically comparable to Adm+/+ placentas and showed (E) highly branched fetal labyrinth vessels, (F) appropriate SA remodeling, and (G) reendothelialization. (H and I) DBA staining revealed that Admhi/hi placentas had a significant 30% increase in uNK cell numbers compared with Adm+/+ littermate placentas. *P < 0.05. Data are mean ± SEM. Scale bars: 1 mm (D); 50 μM (E–H).