biostudies-literature00540Sandovici IMedical Research CouncilNational Institute for Health Research (NIHR)Royal SocietyWellcome TrustBiotechnology and Biological Sciences Research CouncilAcademy of Medical Sciences63-79.e8https://www.ebi.ac.uk/biostudies/studies/S-EPMC8751640biostudies-literatureUnknown57(1)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.Developmental cellThe imprinted Igf2-Igf2r axis is critical for matching placental microvasculature expansion to fetal growth.PMC8751640MC_UU_00014/1MRC_MC_UU_12012/5MRC_MC_UU_12012/4BB/S017593/1MR/R022690/1SBF002\1028MC_UU_12012/5220456/Z/20/ZMC_UU_12012/4BB/H003312/1MC_UU_12012/1DH130036MC_UU_12012/5/BMR/S026193/1MC_UU_00014/5MC_UU_00014/4Schiefer SNSferruzzi-Perri ANBranco CMLam BYHReiterer MFowden ALGeorgopoulou AConstancia MPerez-Garcia VYeo GSHSandovici ILopez-Tello JHoelle KHufnagel ASantos FGaudreau CBurton GJBurling K54falseThe imprinted Igf2-Igf2r axis is critical for matching placental microvasculature expansion to fetal growth.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.2022-01-01T00:00:00Z2022 Jan2024-11-15T21:52:52.964Z2022-02-11T15:10:51.11ZS-EPMC87516403496305810.1016/j.devcel.2021.12.005