Vascular endothelial function and blood pressure homeostasis in mice overexpressing IGF binding protein-1.

IGFs and their binding proteins (IGFBPs) play a significant role in metabolic regulation, and there is growing evidence that they also exert important vascular effects. IGFBP-1 contributes to glucose counterregulation, and observational studies demonstrate an inverse association between circulating IGFBP-1 levels and cardiovascular risk factors. Furthermore, IGFBP-1 levels are lower in subjects with overt macrovascular disease. We therefore hypothesized that IGFBP-1 exerts potentially beneficial effects, either directly or indirectly, on blood pressure regulation and vascular function. We tested this hypothesis using a unique transgenic mouse, which overexpresses human IGFBP-1, and explored the effect of this protein on metabolic, blood pressure, and vascular homeostasis. IGFBP-1-overexpressing mice exhibited postprandial hyperinsulinemia with preservation of glucocompetence and insulin sensitivity. Blood pressure was unchanged in the fasting state but was significantly lower in transgenic mice after a carbohydrate load. Aortic rings from IGFBP-1-overexpressing mice were hypocontractile in response to vasoconstrictors, and relaxation responses were unimpaired. Basal nitric oxide production was increased and endothelial nitric oxide synthase mRNA expression upregulated in aortae of these mice. Our data suggest that IGFBP-1 plays an important and potentially beneficial role in regulating metabolic and vascular homeostasis.

The relationship among circulating insulin-like growth factor (IGF)-I, IGF-binding proteins-1 and -2, and birth anthropometry: a prospective study.

Fetal IGF-I is a determinant of birth weight, but whether maternal IGF-I plays a significant role is controversial. We sought to examine the relationships among maternal IGF-I, IGF-binding protein (IGFBP)-1, and IGFBP-2, with maternal and newborn anthropometry, in a cohort of 325 nondiabetic pregnant women of African origin. Blood was collected for IGF-I, IGFBP-1, and IGFBP-2 at 9, 25, and 35 wk gestation and in cord blood at delivery. In the second and third trimesters, maternal IGF-I was significantly correlated (P < 0.005) with maternal body mass index and triceps skinfold thickness. Maternal IGFBP-1 and -2 had an inverse correlation (P < 0.0001), with maternal anthropometry. Maternal IGF-I at 35 wk, and fetal IGF-I by cord blood were significantly correlated with birth weight (P = 0.001 and 0.048, respectively). IGFBP-1 in the third trimester and cord blood were negatively correlated with birth weight (P = 0.012 and 0.002). In multiple regression analyses, maternal IGF-I at 35 wk, fetal IGF-I, maternal weight at the first antenatal visit, gender, and gestational age were significant independent factors in the determination of birth weight. In conclusion, maternal IGF-I levels, especially during late pregnancy, positively influence birth weight.

Altered placental development and intrauterine growth restriction in IGF binding protein-1 transgenic mice.

IGF binding protein-1 (IGFBP-1) is a secretory product of decidualized endometrium and a major constituent of amniotic fluid. It is thought to modulate the actions of the IGFs on trophoblast cells and is therefore potentially important in regulating placental development and fetal growth. To investigate this hypothesis, we have studied the effects of decidual IGFBP-1 excess on fetoplacental growth in transgenic mice overexpressing human IGFBP-1. Endogenous fetal IGFBP-1 overexpression is associated with a transient impairment of fetal growth in midgestation. Maternal decidual IGFBP-1 excess is also associated with impaired fetal growth in midgestation independent of fetal genotype, indicating placental insufficiency. Our data also demonstrate that amniotic fluid IGFBP-1 is derived almost exclusively from maternal sources. Decidual IGFBP-1 overexpression has a marked effect on placental development. Placental morphology is abnormal in transgenic females due to altered trophoblast invasion and differentiation. These changes result in an increase in placental mass throughout pregnancy. This study provides the first compelling in vivo evidence that IGFBP-1 plays a role in placentation and suggests that IGFBP-1 has a pathological role in preeclampsia, a disorder characterized by shallow uterine invasion and altered placental development.