Macrophages regulate corpus luteum development during embryo implantation in mice
Alison S. Care, … , Wendy V. Ingman, Sarah A. Robertson
Alison S. Care, … , Wendy V. Ingman, Sarah A. Robertson
Published July 8, 2013
Citation Information: J Clin Invest. 2013;123(8):3472-3487. https://doi.org/10.1172/JCI60561.
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Research Article Reproductive biology

Macrophages regulate corpus luteum development during embryo implantation in mice

Abstract

Macrophages are prominent in the uterus and ovary at conception. Here we utilize the Cd11b-Dtr mouse model of acute macrophage depletion to define the essential role of macrophages in early pregnancy. Macrophage depletion after conception caused embryo implantation arrest associated with diminished plasma progesterone and poor uterine receptivity. Implantation failure was alleviated by administration of bone marrow–derived CD11b+F4/80+ monocytes/macrophages. In the ovaries of macrophage-depleted mice, corpora lutea were profoundly abnormal, with elevated Ptgs2, Hif1a, and other inflammation and apoptosis genes and with diminished expression of steroidogenesis genes Star, Cyp11a1, and Hsd3b1. Infertility was rescued by exogenous progesterone, which confirmed that uterine refractoriness was fully attributable to the underlying luteal defect. In normally developing corpora lutea, macrophages were intimately juxtaposed with endothelial cells and expressed the proangiogenic marker TIE2. After macrophage depletion, substantial disruption of the luteal microvascular network occurred and was associated with altered ovarian expression of genes that encode vascular endothelial growth factors. These data indicate a critical role for macrophages in supporting the extensive vascular network required for corpus luteum integrity and production of progesterone essential for establishing pregnancy. Our findings raise the prospect that disruption of macrophage-endothelial cell interactions underpinning corpus luteum development contributes to infertility in women in whom luteal insufficiency is implicated.

Authors

Alison S. Care, Kerrilyn R. Diener, Melinda J. Jasper, Hannah M. Brown, Wendy V. Ingman, Sarah A. Robertson

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Figure 5

Infertility in macrophage-depleted Cd11b-Dtr mice is associated with structural demise of corpora lutea.

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Infertility in macrophage-depleted Cd11b-Dtr mice is associated with str...
(A) Sections of ovary (low power, stained with hematoxylin) from macrophage-depleted Cd11b-Dtr mice collected on day 4.5 pc, 24 hours following i.p. injection of DT (25 ng/g), showed abnormal interstitial spaces within most corpora lutea (arrowheads). Sections of corpora lutea (inserts are high power, stained with H&E) were filled with red blood cells (arrows) and show atypical structure compared with wild-type control mice given DT. Scale bars: 50 μm. (B–E) Expression of genes involved in luteolysis, hypoxia, and inflammation, including (B) Ptgs2 (Cox2), (C) Hif1a, (D) Il6, and (E) Tnfa, was upregulated in ovaries of Cd11b-Dtr mice on days 1.5, 2.5, and 4.5 pc, 24 hours after DT injection, compared with wild-type mice given DT. (F) Expression of genes regulating apoptosis, including Hsp90aa1 and Bax, was upregulated on day 4.5 pc 24 hours after DT injection, while expression of Bcl2 and Hsp90aa2 was unchanged. All genes were quantified by RT-PCR and normalized to Actb expression (n = 7–8 mice per group). Data are mean ± SEM relative to wild-type expression at day 1.5 (B–E) or day 4.5 (F). #P = 0.06, *P < 0.05, **P < 0.01, ***P < 0.001, Cd11b- +DT versus WT +DT.