Intrauterine growth restriction in humans is associated with abnormalities in placental insulin-like growth factor signaling

The IGFs promote the growth and development of the feto- placental unit during gestation, and impairment of their pla- cental actions may result in altered intrauterine growth of the fetus. In this study, proteins involved in IGF signaling were investigated in human placentas from pregnancies compli- cated by intrauterine growth restriction (IUGR) compared with those from normal pregnancies. IUGR placentas exhib- ited 33% reduction in the protein content of IGF-I receptors, but no changes in insulin receptor protein levels. In addition, insulin receptor substrate-2 (IRS-2) protein levels were re- duced in IUGR placentas, with no changes in IRS-1 or Shc protein content, and this was associated with a parallel de- crease in IRS-2-associated phosphatidyl inositol 3-kinaseAkt protein expression was also reduced in IUGR, whereas phosphorylation of Akt and its substrate glycogen synthase kinase-3 was unchanged. Finally, in IUGR placentas there was impaired activation of multiple members of the MAPK family, because phosphorylation of p38 and c-Jun N-terminal kinase was reduced 70%. In conclusion, human placentas from preg- nancies complicated by IUGR are characterized by decreased IGF-I receptor content, selective impairment of the IRS-2/ phosphatidyl inositol 3-kinase pathway, and reduced p38 and c-Jun N-terminal kinase activation. The observed abnormal- ities in IGF-I signaling may contribute to altered fetal growth and development in human IUGR. (Endocrinology 146: 1498 –1505, 2005)