title: Intrauterine growth restriction in humans is associated with abnormalities in placental insulin-like growth factor signaling.
abstract: 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.
authors.affiliation: 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.
authors.forename: Luigi
authors.initials: L
authors.lastname: Laviola
authors.forename: Sebastio
authors.initials: S
authors.lastname: Perrini
authors.forename: Gaetana
authors.initials: G
authors.lastname: Belsanti
authors.forename: Annalisa
authors.initials: A
authors.lastname: Natalicchio
authors.forename: Carmela
authors.initials: C
authors.lastname: Montrone
authors.forename: Anna
authors.initials: A
authors.lastname: Leonardini
authors.forename: Antonella
authors.initials: A
authors.lastname: Vimercati
authors.forename: Marco
authors.initials: M
authors.lastname: Scioscia
authors.forename: Luigi
authors.initials: L
authors.lastname: Selvaggi
authors.forename: Riccardo
authors.initials: R
authors.lastname: Giorgino
authors.forename: Pantaleo
authors.initials: P
authors.lastname: Greco
authors.forename: Francesco
authors.initials: F
authors.lastname: Giorgino
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001724:Birth Weight; D001835:Body Weight; D049109:Cell Proliferation; D004789:Enzyme Activation; D005260:Female; D005317:Fetal Growth Retardation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007231:Infant, Newborn; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D009929:Organ Size; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D010920:Placenta / Q000002:abnormalities* / Q000378:metabolism; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D013002:Somatomedins / Q000378:metabolism*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D038362:Glycogen Synthase Kinase 3; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; D055765:Shc Signaling Adaptor Proteins; D013002:Somatomedins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C526297:IRS2 protein, human; C528024:SHC1 protein, human; C494918:AKT1 protein, human