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.
View: Text | PDF
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

×

Figure 7

Infertility in macrophage-depleted Cd11b-Dtr mice is rescued by administration of exogenous progesterone.

Options: View larger image (or click on image) Download as PowerPoint
Infertility in macrophage-depleted Cd11b-Dtr mice is rescued by administ...
(A) Deciduoma formation was unchanged in Cd11b-Dtr mice given DT to deplete macrophages, compared with PBS-treated control Cd11b-Dtr mice. Deciduoma formation was measured after oil instillation into the left uterine horn (arrows), following ovariectomy and exogenous progesterone and estrogen replacement to mimic the physiological hormone environment of early pregnancy. (B) The fold-change in weight due to deciduoma (weight of oil-treated uterine horn / weight of control uterine horn) was comparable in Cd11b-Dtr mice given DT or PBS. (C) Alkaline phosphatase staining to detect decidual cells in sections of uterus from the oil-instilled left horn of the uterus showed a similar area of deciduoma in DT-treated and PBS-treated Cd11b-Dtr mice, with no deciduoma in the right, control horn. Scale bars: 200 μm. (D) At autopsy on day 7.5 pc, macrophage-depleted Cd11b-Dtr mice had normal implantation sites (arrow) when progesterone (P4) was administered following injection of DT (25 ng/g) on day 3.5 pc, compared with absence of implantation sites in macrophage-depleted Cd11b-Dtr mice given vehicle (veh; left panel). (E) The number of implantation sites per mouse is shown for wild-type mice (WT +DT) and macrophage-depleted Cd11b-Dtr mice (Cd11b- +DT) administered DT on day 3.5 pc, followed by progesterone or vehicle. Data represent the number of implantations per mouse, with mean ± SEM superimposed. The number of mice in each group is shown in parentheses. *P < 0.0001, Cd11b- +DT versus WT +DT.