Abstract
Growth of a fetus is dependent upon the functional capacity of its placenta, but how the latter is matched to fetal demands is currently unknown. Critically, there is continuous expansion of the feto-placental microvasculature throughout pregnancy, along with morphogenic modifications in the overlying trophoblast epithelium. Here we demonstrate, through fetal and trophoblast specific genetic manipulations in the mouse, that signalling by IGF2 from the feto-placental endothelium and endocrine actions of circulating fetal IGF2 are required. We provide evidence that endothelial and fetal-derived IGF2 plays an important role in trophoblast morphogenesis, acting through Gcm1 and Synb. The effects on placental microvasculature expansion are mediated through IGF2R and angiopoietin-Tie2/TEK signalling. Thus, our study reveals a direct role for IGF2-IGF2R axis on matching fetal demand to placental supply and establishes the principle that hormone-like signals from the fetus play important roles in the control of placental vascularization and trophoblast morphogenesis, findings that have potential clinical implications.
