The imprinted Igf2-Igf2r axis is critical for matching placental microvasculature expansion to fetal growth.
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Peer-reviewed
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Abstract
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.
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1878-1551
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Medical Research Council (MC_UU_12012/4)
Medical Research Council (MC_UU_12012/5)
Medical Research Council (MR/R022690/1)
Medical Research Council (MC_UU_12012/1)
MRC (MR/S026193/1)
MRC (MC_UU_00014/1)
MRC (MC_UU_00014/4)
MRC (MC_UU_00014/5)
Biotechnology and Biological Sciences Research Council (BB/S017593/1)
Wellcome Trust (220456/Z/20/Z)
Medical Research Council (MC_PC_12012)