ESA-SRB-AOTA 2019

Reduction in regulatory T cell number in early pregnancy impairs decidual artery remodeling and leads to fetal growth restriction (#221)

Alison S Care 1 2 3 , Holly M Groome 1 , Sandra T Davidge 2 3 , Sarah A Robertson 1
  1. Robinson Research Institute and Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
  2. Women and Children's Health Research Institute, Edmonton, AB, Canada
  3. Department of Obstetrics and Gynaecology, University of Alberta, Edmonton, AB, Canada

INTRODUCTION: Preeclampsia is an important cause of maternal and perinatal morbidity and mortality, and increases the susceptibility of the mother and offspring to cardiovascular disease later in life. In preeclampsia, a deficiency in regulatory T (Treg) cells has been observed. Treg cells prevent maternal immune rejection of the fetus, and suppress inflammatory activation. We have shown they also contribute to uterine vascular function in pregnant mice (Care et al Hypertension 2018), consistent with emerging roles in systemic vascular homeostasis. In particular, Treg cell deficiency causes impaired uterine artery function in mid-pregnancy. We hypothesise that a reduced Treg cell population will alter uteroplacental haemodynamics in late gestation, affecting fetal and placental development.

METHODS: Transgenic Foxp3-DTR mice have FOXP3 promoter-driven expression of the human diphtheria toxin (DT) receptor to enable selectively depletion of FOXP3+ (Treg) cells. DT was injected (37.5ng/g) on gestational day (GD)3.5 and GD5.5 to selectively deplete FOXP3+ cells; vehicle-treated Foxp3-DTR mice served as controls. Morphometric analysis of decidual spiral arteries was conducted on day GD10.5, ultrasound biomicroscopy and fetal biometrics were assessed on GD18.5.

RESULTS: Following DT-treatment to deplete Treg cells, decidual spiral artery remodeling was impaired on GD10.5, with a 20% smaller diameter compared to control mice (P<0.05). In late pregnancy (GD18.5) uterine artery hemodynamics were perturbed, with the pulsatility index increased by 20% (P<0.05). Furthermore, male and female fetuses were growth restricted, being 15-18% lighter (P<0.05), and female fetuses had a shorter abdominal girth. The fetal:placental weight ratio, a surrogate measure of placental efficiency, was reduced in placentas from male and female fetuses.

CONCLUSION: We demonstrate an essential role for Treg cells in fetal growth and uteroplacental vascular function. Given the severe implications of preeclampsia on the future health of the mother and her baby, investigation of therapeutic strategies targeting Treg cells offers a promising intervention.