Höfundar:
Guðrún Valdimarsdóttir, Halla Ingólfsdóttir, Þóra Steingrímsdóttir
During normal pregnancy, fetal trophoblasts invade the maternal decidual spiral arteries and replace the endothelium. This remodelling of high- to low-resistance vessels provides the placenta with adequate perfusion by an as yet unknown molecular mechanism. To achieve this process, the cytotrophoblasts first need to undergo epithelial-to-mesenchymal transition (EMT) during differentiation and invasion and then to undergo mesenchymal-to-endothelial transition (MEndT) during the arterial remodelling.
The Transforming Growth Factor-beta (TGFbeta) family plays a pivotal role in placental development but is very conflicting. We found that SNAIL is highly associated with the invasive properties of human TBs. Moreover, the induction of SNAIL is mediated through a combinatorial mechanism of the TGFbeta receptors, ALK5/ALK2. We discovered that SMAD1/5 phosphorylation occurs transiently via the type I receptors ALK2 and ALK5, leading to induced TB migration. Unexpectedly, TGFbeta, but not BMP induced this effect. SMAD1/5 phosphorylation and expression of SNAIL is reduced in placenta from Preeclamtic donors compared to healthy donors whereas SMAD2/3 phosphorylation and Thrombospondin-1 expression is increased. Our results suggests that TGFbeta transiently induces SNAIL via ALK2 in a combination with ALK5. Extravillous trophoblasts may utilize the transient TGFbeta-induced ALK2/SMAD1/5 signalling to enter transient epithelial-mesenchymal transition (EMT) to enable subsequent mesenchymal-endothelial transition (MEndT) along the differentiation trajectory towards pseudo-endothelial cells.