Endocrine Abstracts

Fetal growth restriction is associated with abnormal placental cell (cytotrophoblast) proliferation. Using an explant model of human first trimester placenta, we have demonstrated that the IGFI and -II stimulate proliferation in cytotrophoblast and are probably essential for normal placental growth. IGF activates signalling through both Akt and ERK, so the regulation of these pathways in placenta is important for normal pregnancy outcome. The tissue contains high levels of mic...

Pregnancy complications such as pre-eclampsia and intrauterine growth restriction are associated with abnormal placental cell (cytotrophoblast; CT) proliferation and apoptosis. The mechanisms regulating these events are unclear however altered levels of IGFs have also been reported in these conditions. Using an explant model of human first trimester placenta we have shown that both IGF-I and –II act through IGF1R mediated signalling pathways to enhance CT proliferation, d...

IGF-I and -II influence cytotrophoblast proliferation by activating the type-I IGF receptor (IGF1R) in first trimester human placenta. Ligand access to receptors is regulated by IGF binding proteins (IGFBPs) 1-6. In humans, the most abundant IGFBPs at the maternal-fetal interface are IGFBP-1 and IGFBP-3; we hypothesised that these IGFBPs function to regulate the effects of IGFs in the placenta and used our placental explant model, in which proliferation and differentiation are...

Successful implantation requires the synchronisation of viable embryonic development with endometrial receptivity. The mechanisms allowing for the initiation of crosstalk remain elusive, however recent studies have revealed alterations in endometrial microRNAs (miRs) in women suffering repeated implantation failure (RIF). We hypothesised that the IGF1 receptor (IGF1R) is involved in implantation, and that miR145, which is elevated in RIF endometrium and predicted to target IGF...

The in utero environment is crucial for both the prenatal and long-term health of the offspring. The placenta is able to modify its structure/function in response to maternal growth and nutritional signals to actively regulate maternal-to-fetus nutrient transfer and consequently optimum fetal development. Little is known about the molecular mechanisms involved in placental sensing of maternal nutrients. However, we postulate that nutrient flux through the hexosamine biosynthet...

Fetal growth restriction and overgrowth (macrosomia) are both associated with altered placental development and problems at birth. Both conditions have lifelong impacts on health including an increased risk of developing cardiovascular disease and diabetes. Placental development depends on co-ordinated cellular growth and is enhanced by maternally-derived growth factors. MicroRNAs (miRs) are known to regulate gene expression and we have shown that global miR suppression in pla...

Pregnancy complications such as fetal growth restriction are associated with abnormal placental cell (cytotrophoblast) proliferation and apoptosis. Regulation of these events is unclear but recently we have used a placental explant model to demonstrate that IGFs influence cytotrophoblast kinetics and demonstrated that the protein tyrosine phosphatase (PTP) SHP-2 is required for IGF actions in the placenta. However, SHP-2 accounts for only 20% of total PTP activity, suggesting ...

IGF1 plays a central role in placental growth. IGF delivered from maternal circulation binds to the IGF1 receptor (IGF1R) in syncytium resulting in the activation of Akt; inhibition of this pathway affects cytotrophoblast turnover. However, the route(s) by which IGF1 enters placenta and how its signal is delivered into the two trophoblast compartments is unknown. We have utilised quantum dots (QDs) to deliver/track IGF1 binding and internalisation in first trimester placenta (...

Mutations in the leptin receptor gene (Lepr) occur spontaneously in humans and mice and are linked to early onset obesity and diabetes. Mice heterozygous for a signalling-deficient receptor (db/+) are widely used as a model of gestational diabetes that results in fetal macrosomia, but the contribution of the fetal genotype has yet to be evaluated. Eight week old wild type (wt) females (n=8) were mated to db/+ males and db/+ females (n=10) were mated to wt males i...

Abnormal fetal growth remains a problem in pregnancies, complicated by diabetes and is associated with increased maternal and offspring mortality and morbidity. Insulin-like growth factors (IGFs) are important regulators of fetal growth. Their effects are controlled by binding proteins (IGFBPs). IGFBP-1 is particularly important in pregnancy. Phosphorylated IGFBP-1 (pIGFBP-1) has a high affinity for IGF-I and inhibits IGF-I actions, whereas de-phosphhorylated IGFBP-1 has a low...