Macrophages regulate corpus luteum development during embryo implantation in mice
Alison S. Care, Kerrilyn R. Diener, Melinda J. Jasper, Hannah M. Brown, Wendy V. Ingman, Sarah A. Robertson
Alison S. Care, Kerrilyn R. Diener, Melinda J. Jasper, Hannah M. Brown, Wendy V. Ingman, Sarah A. Robertson
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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 4

Infertility in macrophage-depleted Cd11b-Dtr mice results from implantation failure.

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Infertility in macrophage-depleted Cd11b-Dtr mice results from implantat...
(A) Trypan blue clearly delineates bands of increased vascular permeability in the uterus, showing embryo implantation sites in some, but not all, macrophage-depleted Cd11b-Dtr mice (arrows) on day 4.5 pc (upper right), 24 hours after i.p. injection with DT (25 ng/g) on day 3.5 pc, compared with the majority of wild-type mice given DT (upper left). By day 5.5 pc, 48 hours after DT injection, no evidence of implantation was observed in any Cd11b-Dtr mice compared with normal implantation sites in wild-type mice. (B) The numbers of implantation sites per mouse at day 4.5 pc and day 5.5 pc are shown for wild-type mice (WT +DT) and macrophage-depleted Cd11b-Dtr mice (Cd11b- +DT), after injection of DT on day 3.5 pc. Data are number of implantations per mouse, with mean ± SEM superimposed. The number of mice per group is shown in parentheses. *P < 0.05, ** P < 0.01, Cd11b- +DT versus WT +DT. (C) Sections of uterus (H&E) from Cd11b-Dtr mice on day 4.5 pc (24 hours following DT injection) show that blastocyst-stage embryos (arrows) were attached laterally or in the middle of an open lumen with no decidual zone (10/12 embryos; middle panel), or less frequently were attached with a decidual zone, but incomplete uterine closure (2/12 embryos; right panel). This compared with wild-type mice, in which typical implantation sites in a narrowed endometrial lumen, with surrounding decidual zone, were consistently evident (left panel). Images are representative of 10–12 embryos in 4 WT and 5 Cd11b-Dtr mice. Insets are high-power. Lu, lumen; ICM, inner cell mass; TE, trophectoderm; DZ, decidual zone. Scale bars: 50 μm.