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Intrauterine Growth Restriction in Humans Is Associated with Abnormalities in Placental Insulin-Like Growth Factor Signaling

Department of Emergency and Organ Transplantation, Section on Internal Medicine, Endocrinology and Metabolic Diseases (L.L., S.P., G.B., A.N., C.M., A.L., R.G., F.G.), and Department of Obstetrics and Gynecology, Clinica Ostetrica e Ginecologica II (A.V., M.S., L.S.), University of Bari, I-70124 Bari, Italy; and Department of Obstetrics and Gynecology, University of Foggia (P.G.), I-71100 Foggia, Italy

Address all correspondence and requests for reprints to: Dr. Francesco Giorgino, Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology and Metabolic Diseases, University of Bari, Piazza Giulio Cesare 11, I-70124 Bari, Italy. E-mail: f.giorgino{at}endo.uniba.it.

The IGFs promote the growth and development of the feto-placental unit during gestation, and impairment of their placental 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 complicated by intrauterine growth restriction (IUGR) compared with those from normal pregnancies. IUGR placentas exhibited 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 reduced in IUGR placentas, with no changes in IRS-1 or Shc protein content, and this was associated with a parallel decrease in IRS-2-associated phosphatidyl inositol 3-kinase. Akt 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 pregnancies 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 abnormalities in IGF-I signaling may contribute to altered fetal growth and development in human IUGR.

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