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.

Nutritional manipulation between early to mid-gestation: effects on uncoupling protein-2, glucocorticoid sensitivity, IGF-I receptor and cell proliferation but not apoptosis in the ovine placenta

“…This coincided with the stage at which mean placentome mass was reduced and is in accord with findings in rats and humans in which intrauterine growth retardation is accompanied with reduced placental IGF-IR (Reid et al 2002, Laviola et al 2005. It should be noted, however, that the placenta is markedly different between sheep, rats, and humans which have discoid, hemochorial placenta, whereas in sheep placenta are cotyledonary synepitheliochorial that may represent an evolutionary development and can limit the transport of some molecules from the mother to fetus (Carter & Mess 2007).…”

“…These include a reduction in the plasma concentrations of a range of maternal metabolic hormones including cortisol, thyroid hormones, insulin-like growth factor (IGF)-I, and insulin (Bispham et al 2003, Symonds et al 2007. A reduction in placental IGF type-I receptor (IGF-IR) is associated with intrauterine growth retardation (Reid et al 2002, Laviola et al 2005. The extent to which the same effect on the IGF-IR may result from changes in maternal nutrition is unknown and was a further aim of the present study.…”

The IGF Axis in Baboon Pregnancy: Placental and Systemic Responses to Feeding 70% Global Ad Libitum Diet

“…Maternal IGF-I in its bound form does not cross the placental barrier in rats; however, the placenta transports free IGF [36]. IGF-I gene expression is high in the human placenta at term, but the corresponding protein is undetectable [37,38]. In agreement with data published by Carter and Han, IGF-I mRNA expression in our study was detected in syncytiotrophoblast [5].…”

Genetic disorders in the GH–IGF-I axis in mouse and man

“…However, in a recent study by Laviola et al, the IRS-2 and Akt pathways were down-regulated in human placentas from pregnancies complicated by IUGR, indicating an important role for IGF-I signaling in the appropriate development of the fetoplacental unit (31).…”