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

Depletion of regulatory T cells alters the uterine artery function during pregnancy and causes fetal growth restriction (#34)

Alison S Care 1 2 3 , Stephane L Bourque 3 4 , Emma P Hjartarson 2 3 , Sarah A Robertson 1 , Sandra T Davidge 2 3
  1. Robinson Research Institute and Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
  2. Department of Obstetrics and Gynaecology, University of Alberta, Edmonton, AB, Canada
  3. Women and Children's Health Research Institute, Edmonton, AB, Canada
  4. Department of Anaesthesiology and Pain Medicine, University of Alberta, Edmonton, AB, Canada

Regulatory T (Treg) cells prevent maternal immune rejection of the fetus and fewer circulating Treg cells are associated with pregnancy complications. We hypothesise that a reduced Treg cell population causes uterine artery dysfunction. We propose that this occurs via increased matrix metalloproteinase (MMP)-2-induced cleavage of the inactive precursor big endothelin-1 (ET-1) to the active vasoconstrictor, ET-1. FOXP3 is a key transcription factor in Treg cells. Pregnant mice with FOXP3 promoter-driven expression of the human diphtheria toxin (DT) receptor (Foxp3-DTR mice) were injected with DT (37.5ng/g) on gestational day (GD)3.5 and GD5.5 to selectively deplete FOXP3+ cells; DT-treated C57BL/6J mice as controls. FOXP3+ cell depletion was measured using flow cytometry. Uterine artery function was assessed ex-vivo on GD10.5 using wire myography. In a separate group, fetal biometrics were assessed on GD17.5. Following DT treatment, FOXP3 expression in uterine draining lymph nodes was reduced by 89% in Foxp3-DTR mice compared to wild-type mice (p<0.001). On GD10.5, Foxp3-DTR mice had increased fetal resorption (wild-type+DT: 0.1±0.1 resorptions, Foxp3-DTR+DT: 2.3±0.6; p<0.001). In late pregnancy, Treg cell depletion caused fetal growth restriction (wild-type+DT: 980.9±16.4mg, Foxp3-DTR: 854.4±48.1mg; p=0.01). Uterine artery conversion of bigET-1 to active ET-1 was enhanced following Treg cell depletion (p<0.001). The MMP-inhibitor GM6001 reduced uterine artery vasoconstriction by 36% in wild-type mice, but vasoconstriction was unaffected by Treg depletion. Maximal ET-1-induced constriction in the uterine artery was unchanged by Treg cell depletion (% of phenylephrine maximal constriction, wild-type+DT: 111.2±4.4, Foxp3-DTR+DT: 119.6±8.4; p=0.42). In summary, Treg cell-depletion caused fetal growth restriction, increased fetal resorption and increased uterine artery responses to bET-1. MMP-induced conversion of bigET-1 to active ET-1 was reduced only in wild-type mice, contrary to our hypothesis. These data suggest that bigET-mediated pathways are dysregulated following Treg depletion, indicating that uterine artery function during pregnancy is regulated by the maternal immune system.