Pancreatic islet hepatocyte growth factor and vascular endothelial growth factor A signaling in growth restricted fetuses

Abstract

Placental insufficiency leads to intrauterine growth restriction (IUGR) and a lifelong risk of developing type 2 diabetes. Impaired islet development in the growth restricted fetus, including decreased β-cell replication, mass, and insulin secretion, is strongly implicated in the pathogenesis of later life type 2 diabetes. Currently, standard medical management of a woman with a pregnancy complicated by placental insufficiency and fetal IUGR is increased fetal surveillance and indicated preterm delivery. This leads to the dual complications of IUGR and preterm birth - both of which may increase the lifelong risk for type 2 diabetes. In order to develop therapeutic interventions in IUGR pregnancies complicated by placental insufficiency and decrease the risk of later development of type 2 diabetes in the offspring, the mechanisms responsible for impaired islet development in these cases must be determined. This review focuses on current investigations testing the hypothesis that decreased nutrient supply to the IUGR fetus inhibits an intra-islet hepatocyte growth factor - vascular endothelial growth factor A (HGF - VEGFA) feed forward signaling pathway and that this is responsible for developmental islet defects.

Keywords: Hepatocyte growth factor; Insulin; Intrauterine growth restriction; Pancreatic islet; Pregnancy; Vascular endothelial cell growth factor.

Figure 1. Hepatocyte Growth Factor is a necessary and sufficient component of endothelial cell conditioned media to increase islet insulin concentrations

A) Islets from 4 fetuses were divided into endothelial cell (EC) conditioned media (ECCM), ECCM + an inhibitory anti-HGF IgG antibody, and non-conditioned media + HGF (100 ng/mL). Following an overnight incubation the insulin content of the islets was determined and compared to non-conditioned media (dashed line). All conditions included non-specific IgG. * P<0.05. B) Western blotting with the anti-HGF antibody on ECCM demonstrates specificity with a single band (arrow). The entire length of the membrane is shown (indicated by dashed lines). (Rozance et al., 2015)

Figure 2. VEGFA and HGF are lower in PI-IUGR islets and isolated islet endothelial cells, respectively

A) Representative western blots for VEGFA and HGF in pancreatic islet lysates and pancreatic islet endothelial cell lysates, respectively, after loading equal amounts of protein. B) Representative western blot for HGF in EC conditioned media after loading equal volumes of media. C) Quantitative analysis of islet lysate (control, n=10; PI-IUGR, n=4) and islet EC lysates and conditioned media (control, n=3; PI-IUGR, n=4). ** P<0.01. (Rozance et al., 2015)

Figure 3. Media conditioned by isolated PI-IUGR islet ECs does not increase islet insulin content

Islets from 4 fetuses were divided into non-conditioned media and media conditioned by ECs isolated from control (Control ECCM) or PI-IUGR (IUGR ECCM) fetal islets. Following an overnight incubation the islet insulin content was determined and compared to non-conditioned media (dashed line). ** P<0.01. (Rozance et al., 2015)

Figure 4. Intra-islet HGF-VEGFA signaling

Figure 5. cMET and VEGFR2 are the same or higher in PI-IUGR islets and isolated islet ECs

A) Representative western blot for cMet and VEGFR2 in pancreatic islet lysates and pancreatic islet endothelial cell lysates, respectively. B) Quantitative analysis of islet lysate (control, n=10; PI-IUGR, n=4) and islet EC lysates (control, n=3; PI-IUGR, n=4). * P<0.05. (Rozance et al., 2015)