The placenta is a gatekeeper between the mother and fetus, adapting its structure and functions to support optimal fetal growth. Studies exploring adaptations of placentae that support the development of genetically small fetuses are lacking. Here, using a mouse model of impaired fetal growth, achieved by deleting Igf2 (insulin-like growth factor 2) in the epiblast, we assessed placental nutrient transfer and umbilical artery (UA) blood flow during late gestation. At embryonic day (E) 15.5, we observed a decline in the trans-placental flux of glucose (3H-MeG) a nd system A a mino acids (14 C-MeAIB), proportionate with the diminished fetal size, while UA blood flow was normal. However, at E18.5, the trans-placental flux of both tracers was disproportionately decreased and accompanied by blunted UA blood flow. Feto-placental growth and nutrient transfer were more impaired in female conceptuses. Thus, reducing the fetal genetic demand for growth impairs the adaptations in placental blood flow and nutrient transport that normally support the fast fetal growth in late gestation. These findings have important implications for our understanding of the pathophysiology of pregnancies afflicted by fetal growth restriction.This work was supported by the Biotechnology and Biological Sciences Research Council (grant BB/H003312/1 to M.C.), the 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.), the Wellcome Trust (Sir Henry Wellcome Postdoctoral Fellowship 220456/Z/20/Z to J.L.-T.), the Royal Society (Newton International Fellowship grant NF170988/RG90199 to J.L.-T.), Talent Attraction Grant from the Community of Madrid CESAR NOMBELA fellowship (grant No. 2023-T1/SAL-GL-28960); Dorothy Hodgkin Research Fellowship grant (DH130036 to A.N.S.-P.) and the Centre for Trophoblast Research
