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The imprinted Igf2-Igf2r axis is critical for matching placental microvasculature expansion to fetal growth

2021; Elsevier BV; Volume: 57; Issue: 1 Linguagem: Inglês

10.1016/j.devcel.2021.12.005

1878-1551

Ionel Sandovici, Aikaterini Georgopoulou, Vicente Pérez-García, Antonia Hufnagel, Jorge López‐Tello, Brian Lam, Samira Schiefer, Chelsea Gaudreau, Fátima Santos, Katharina Hoelle, Giles S.H. Yeo, Keith Burling, Moritz Reiterer, Abigail L. Fowden, Graham J. Burton, Cristina Branco, Amanda N. Sferruzzi‐Perri, Miguel Constância,

Birth, Development, and Health

In all eutherian mammals, growth of the fetus is dependent upon a functional placenta, but whether and how the latter adapts to putative fetal signals is currently unknown. Here, we demonstrate, through fetal, endothelial, hematopoietic, and trophoblast-specific genetic manipulations in the mouse, that endothelial and fetus-derived IGF2 is required for the continuous expansion of the feto-placental microvasculature in late pregnancy. The angiocrine effects of IGF2 on placental microvasculature expansion are mediated, in part, through IGF2R and angiopoietin-Tie2/TEK signaling. Additionally, IGF2 exerts IGF2R-ERK1/2-dependent pro-proliferative and angiogenic effects on primary feto-placental endothelial cells ex vivo. Endothelial and fetus-derived IGF2 also plays an important role in trophoblast morphogenesis, acting through Gcm1 and Synb. Thus, our study reveals a direct role for the imprinted Igf2-Igf2r axis on matching placental development to fetal growth and establishes the principle that hormone-like signals from the fetus play important roles in controlling placental microvasculature and trophoblast morphogenesis.