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
(A) Embryos flushed on the morning of day 3.5 pc from macrophage-depleted Cd11b-Dtr mice, 24 hours following i.p. injection of DT (25 ng/g), were generally developed to blastocyst stage and often hatched from the zona pellucida, comparable to those flushed from wild-type mice treated with DT. (B) A comparable proportion of embryos flushed from the uterus on day 3.5 pc were developed to morula or blastocyst stage in wild-type or Cd11b-Dtr mice administered DT on day 2.5 pc. (C) Embryos that were flushed from the oviduct on day 0.5 pc (1-cell embryos) of gonadatropin-primed Cd11b-Dtr mice and cultured in the presence of DT (25 ng/ml) for 48 hours, and then without DT for a further 48 hours, developed to blastocyst stage at the same rate as embryos cultured without DT. (D) Embryos flushed from the uterus on day 2.5 pc (8-cell embryos) and cultured with DT (25 ng/ml) for 72 hours developed to blastocyst stage at the same rate as embryos cultured without DT. (B–D) The number of embryos in each group is shown in parentheses. Data are mean ± SEM.