Insulin-like Growth Factor Binding Protein Gene Expression in the Pregnant Rat Uterus and Placenta

Abstract

While the insulin-like growth factor (IGF) system plays a fundamental role in regulating embryonic and placental growth, the specific contributions of the six IGF binding proteins (IGFBPs 1–6) to these processes are not well understood. We here focus on IGFBP expression in the extraembryonic environment, which both supports and constrains embryonic growth, and have usedin situhybridization to determine sites of IGFBP mRNA synthesis in the pregnant rat uterus and placenta. We find that all IGFBPs are expressed in distinct, changing patterns in the uterine endometrium, at the decidual boundary, in the decidual vasculature, and in the myometrium during pregnancy. Within the endometrium, the most prominent change is that expression of IGFBP-1 begins in some, but not all, endometrial glands prior to implantation and then expands to include all secretory epithelia shortly after implantation. During the period of rapid decidual proliferation that follows implantation, IGFBP-3, -4, and -5 transcripts are all detected in a laminar array at the boundary between the decidua and the nondecidualized endometrium. In the decidual vasculature at Day (d) 8.0, both IGFBP-3 and IGFBP-4 mRNAs are detected in dilating blood vessels, with BP-3 most prominent in the antimesometrial plexus and BP-4 primarily at the mesometrial pole. Later (d11.5), all decidual vessels express high levels of IGFBP-3 and lower levels of IGFBP-4 mRNAs. Finally, changes in expression of several IGFBPs also occur within the myometrium during pregnancy. For example, IGFBP-2 is expressed in the inner circular layer shortly after implantation, and expression increases through late gestation. In contrast, IGFBP-5 hybridization occurs over both myometrial layers before implantation, but decreases in intensity and spatial distribution as pregnancy proceeds. Finally, and most strikingly, IGFBP-6 expression, barely detectable in the d7.0 myometrium, gradually increases until it is very strongly transcribed during the placental stages. Taken together, these observations suggest multiple roles for IGFBPs in supporting implantation, regulating the extent of decidualization, modulating local levels of vascular IGFs, and regulating uterine muscular growth.