The relationship between TGFβ, low oxygen and the outgrowth of extravillous trophoblasts from anchoring villi during the first trimester of pregnancy

Abstract

BackgroundDuring the first trimester of human pregnancy, specialised placental cells called extravillous trophoblasts (EVTs) grow out from anchoring villi, invade the maternal decidua and remodel the uterine spiral arteries. Inadequate EVT invasion is associated with pregnancy complications including intrauterine growth restriction (IUGR) and pre-eclampsia. During early pregnancy, the placenta exists in a physiologically normal low oxygen environment, which may regulate EVT outgrowth. One potential oxygen responsive regulator of EVTs is the transforming growth factor-beta (TGFβ) family of cytokines. This work aimed to determine the role of TGFβ1, β2 and β3 in regulating EVT outgrowth in the low oxygen environment of early pregnancy. ResultsUsing a quantitative high-throughput first trimester villous explant model of EVT outgrowth we demonstrated no significant difference in the frequency of EVT outgrowth between explants treated with TGFβ1, β2 or β3. However, explants treated with TGFβ2, but not β1 or β3, produced EVT outgrowths with a significantly smaller area in comparison to untreated controls (p=0.03). When explants were cultured in 1.5% oxygen, TGFβ2, but not β1 or β3, in the conditioned medium of explants that produced EVT outgrowth was significantly reduced in comparison to 8% oxygen (p<0.05). There was no significant difference in the concentration of TGFβ2 or TGFβ3 from isolated primary EVTs cultured in 1.5% or 8% oxygen. ConclusionsTGFβ2 inhibits EVT outgrowth expansion from first trimester anchoring villi. As TGFβ2 secretion from anchoring villi is down-regulated in low oxygen, these findings suggest that the low oxygen environment in early pregnancy may be important to allow EVT outgrowth expansion and promote adequate placentation.