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.