Hypoxia-lnduced Changes in Insulin-Like Growth Factors and Their Binding Proteins in Pregnant Rats

Abstract

Pregnancy is associated with important changes in the insulin-like growth factor (IGF)-insulin-like growth factor binding protein (IGFBP) axis, but the importance of these growth factors for fetal growth is not well understood. We have recently established a maternal hypoxia model that results in significant intrauterine growth retardation in the fetus, and characterized the IGF-IGFBP axis in growth-retarded fetuses. To determine if maternal IGFs and their binding proteins are similarly regulated by hypoxia, we examined their expression in 6 hypoxic dams (13% oxygen, days 14-21 of gestation) and 6 control dams (21 % oxygen). There was no significant difference in the food intake between the groups. The mean body weight of hypoxic dams, however, was 20% less than that of controls. Of all the organs, the lungs were most affected by hypoxia, weighing 17% more in the hypoxic dams than in the control dams; placental weight was reduced by 10% in the hypoxic dams. Liver and brain weights were not changed significantly by hypoxia. The mean concentration of immunoreactive IGF-I was 123 ± 11 ng/ml in the hypoxic dams and 130 ± 18 ng/ml in the control dams (nonsignificant). Similarly, there was no significant difference in hepatic IGF-I mRNA levels determined by solution hybridization nuclease-protection assay. An increase in IGFBP-1, IGFBP-2 and IGFBP-4 concentrations, however, could be observed by Western ligand blotting of the sera of hypoxic dams, compared to control dams. As assessed by Northern blot analysis, there was a 2.8-fold increase in IGFBP-1 mRNA expression in the livers of hypoxic dams compared to controls. Hepatic IGFBP-4 expression was also slightly increased (1.25-fold) in the hypoxic dams. No difference in hepatic IGFBP-2 or IGFBP-3 mRNA was found. Our results show parallel patterns in fetal and maternal IGF and IGFBP responses to hypoxia. This suggests that hypoxia may inhibit fetal growth by both directly affecting the fetus and via inhibition of placental growth.

Insulin‐like growth factor binding protein‐3 suppresses vascular endothelial growth factor expression and tumor angiogenesis in head and neck squamous cell carcinoma

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The role and regulation of IGFBP-1 phosphorylation in fetal growth restriction

“…The fetal liver is the primary source of fetal IGFBP-1 during pregnancy (Watson et al 2006;Tapanainen et al 1997). HepG2 cells have been commonly used as a model for human fetal hepatocytes (Wilkening et al 2003;Kelly and Darlington.…”

Metabolic effects of intermittent hypoxia in mice: steady versus high-frequency applied hypoxia daily during the rest period

“…Previous studies have also shown effects of IH L on energy metabolism via regulation of genes encoding for glucose transporters and glycolytic enzymes (29,61,63), primarily through modulation of hypoxia-inducible factor 1-␣ (HIF-1␣) subunit expression and transcriptional activity. Indeed, HIF-1␣ was reciprocally modulated by insulin and insulin-like growth factor pathways (1,32,69,72,80).…”