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 8

The luteal defect in macrophage-depleted Cd11b-Dtr mice is accompanied by breakdown of the corpus luteum vasculature.

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The luteal defect in macrophage-depleted Cd11b-Dtr mice is accompanied b...
(A–E) Ovaries were recovered from wild-type control or Cd11b-Dtr mice on day 3.5 pc before treatment (A) or on day 4.5 pc, 24 hours after i.p. injection of DT (25 ng/g) (B–E). (A) Sections labeled with MTS-12 to detect blood vessel endothelial cells indicated a substantial network of intact vessels (arrows) in the corpus luteum of both Cd11b-Dtr and wild-type mice on day 3.5 pc. (B) Sections labeled with MTS-12 to detect blood vessel endothelial cells indicated few intact vessels in the corpus luteum of most Cd11b-Dtr compared with wild-type mice, while vessels in the ovarian stroma (arrowheads) and some corpora lutea (arrows) remained intact on day 4.5 pc, following DT injection 24 hours earlier. (C) Sections labeled with antibodies to both CD31 (red) to detect endothelial cells and F4/80 (green) to detect macrophages showed absence of blood vessels in the corpus luteum of Cd11b-Dtr compared with wild-type mice, highlighting the close spatial association between endothelial cells and macrophages (inset is high power). (D) In sections labeled with both CD31 and F4/80, cells co-expressing both markers (arrows) were evident. (E) Sections labeled with LYVE-1 (red) to detect lymphatic endothelial cells showed lymphatic vessels at the margins of a corpus luteum of Cd11b-Dtr mice, similar to wild-type mice. Photomicrographs are representative of 6–7 mice per group. Scale bars: 50 μm.