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

Dev Cell. 2022 Jan 10;57(1):63-79.e8. doi: 10.1016/j.devcel.2021.12.005. Epub 2021 Dec 27.


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.

Keywords: IGF2; IGF2R; angiogenesis; angiopoietins; development; endothelial cells; fetal growth; genomic imprinting; placenta; trophoblast morphogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • DNA-Binding Proteins / genetics
  • Endothelial Cells / metabolism
  • Female
  • Fetal Development
  • Fetus / metabolism
  • Insulin-Like Growth Factor II / genetics
  • Insulin-Like Growth Factor II / metabolism*
  • Insulin-Like Growth Factor II / physiology
  • Mice
  • Mice, Inbred C57BL
  • Microvessels / metabolism
  • Neovascularization, Physiologic / physiology
  • Placenta / blood supply*
  • Placenta / metabolism
  • Placenta / physiology
  • Placentation
  • Pregnancy
  • Receptor, IGF Type 2 / metabolism*
  • Receptor, IGF Type 2 / physiology
  • Transcription Factors / genetics
  • Trophoblasts / metabolism


  • DNA-Binding Proteins
  • IGF2 protein, mouse
  • Igf2r protein, mouse
  • Receptor, IGF Type 2
  • Transcription Factors
  • Insulin-Like Growth Factor II