The 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.This work was supported by Biotechnology and Biological Sciences Research Council (grant BB/H003312/1 to M.C.), Medical Research Council (MRC_MC_UU_12012/4 to M.C.; MRC_MC_UU_12012/5 to the MRC Metabolic Diseases Unit; MR/R022690/1 to A.N.S-P.), Spanish Ministry of Science and Innovation (RYC-2019-026956 and PID2020-114459RA-I00 to V.P-G.), Wellcome Trust (Sir Henry Wellcome Postdoctoral Fellowship 220456/Z/20/Z to J.L-T.), Royal Society (Dorothy Hodgkin Research Fellowship grant DH130036 to A.N.S-P.), Centre for Trophoblast Research and the NIHR Cambridge BRC Cell Phenotyping Hub