HYPOXIA-INDUCED CHANGES IN INSULIN-LIKE GROWTH-FACTORS AND THEIR BINDING-PROTEINS IN PREGNANT RATS

Pregnancy is associated with important changes in the insulin-like gro wth factor (IGF)-insulin-like growth factor binding protein (IGFBP) ax is, but the importance of these growth factors for fetal growth is not well understood. We have recently established a maternal hypoxia mode l that results in significant intrauterine growth retardation in the f etus, and characterized the IGF-IGFBP axis in growth-retarded fetuses. To determine if maternal IGFs and their binding proteins are similarl y 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 g roups. The mean body weight of hypoxic dams, however, was 20% less tha n 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 da rns; placental weight was reduced by 10% in the hypoxic dams. Liver an d brain weights were not changed significantly by hypoxia. The mean co ncentration of immunoreactive IGF-I was 123 +/- 11 ng/ml in the hypoxi c dams and 130 +/- 18 ng/ml in the control dams (nonsignificant). Simi larly, there was no significant difference in hepatic IGF-I mRNA level s determined by solution hybridization nuclease-protection assay. An i ncrease in IGFBP-1, IGFBP-2 and IGFBP-4 concentrations, however, could be observed by Western ligand blotting of the sera of hypoxic dams, c ompared 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 hy poxic dams compared to controls. Hepatic IGFBP-4 expression was also s lightly increased (1.25-fold) in the hypoxic dams. No difference in he patic IGFBP-2 or IGFBP-3 mRNA was found. Our results show parallel pat terns in fetal and maternal IGF and IGFBP responses to hypoxia. This s uggests that hypoxia may inhibit fetal growth by both directly affecti ng the fetus and via inhibition of placental growth.