Poster Presentation The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2017

Macrophage regulation of vascular remodelling is required for placental development in mice (#316)

Holly M Groome 1 2 , Peck Yin Chin 1 2 , Ella S Green 1 2 , Rebecca L Wilson 1 2 , Claire T Roberts 1 2 , Sarah A Robertson 1 2
  1. The Robinson Research Institute, Adelaide, SA, Australia
  2. The University of Adelaide, Adelaide, SA, Australia

Successful pregnancy requires specific maternal immune cells to tolerate and support development of the semi-allogenic fetus. In particular, macrophages of both the M1 and M2 phenotypes have been implicated in suppressing inflammation, promoting immune tolerance, regulating angiogenesis and vascular remodelling, and may be crucial for successful pregnancy. We hypothesised that macrophages are crucial for placental morphogenesis, specifically through regulating vascular changes required for normal placental development and function. To assess this, a murine macrophage depletion model, CD11b-dtr, was utilised wherein mice express the diphtheria toxin (DT) receptor (DTR) under the control of the CD11b promoter causing transient ablation of CD11b+ cells upon DT treatment. CD11b-dtr or FVB wild-type females were mated to Balb/c stud males, and administered DT on day 5.5 post coitum (pc) at two doses, 10 ng/g or 25 ng/g. Control mice, CD11b-dtr females, received PBS. Flow cytometry assessment at 24 hr post DT treatment confirmed that 25 ng/g DT elicited significant macrophage depletion in the peritoneum, spleen and uterus, whereas 10 ng/g DT treatment elicited partial depletion. In a separate cohort, pregnancy outcomes and placental morphology were assessed on day 17.5 pc (n=10-12 mice per group). High dose DT resulted in 90% pregnancy failure at day 17.5 pc whereas low dose DT resulted in 40% pregnancy failure, compared to <10% in control groups. Implantation sites in the 10 ng/g DT group revealed growth restriction in fetuses (18% reduction; p ≤0.001) as well as an increase in placental weights (8% increase; p ≤0.001). Immunohistochemical analysis revealed altered structure of the placental labyrinthine region, associated with reduced fetal vasculature and increased trophoblast surface area, indicating a less efficient placenta. In summation, macrophage depletion on day 5.5 pc impairs placental development and compromises fetal health. These results demonstrate that macrophages are key regulators of placental development and pregnancy success.