title: Placental insufficiency decreases pancreatic vascularity and disrupts hepatocyte growth factor signaling in the pancreatic islet endothelial cell in fetal sheep.
abstract: Hepatocyte growth factor (HGF) and vascular endothelial growth factor A (VEGFA) are paracrine hormones that mediate communication between pancreatic islet endothelial cells (ECs) and β-cells. Our objective was to determine the impact of intrauterine growth restriction (IUGR) on pancreatic vascularity and paracrine signaling between the EC and β-cell. Vessel density was less in IUGR pancreata than in controls. HGF concentrations were also lower in islet EC-conditioned media (ECCM) from IUGR, and islets incubated with control islet ECCM responded by increasing insulin content, which was absent with IUGR ECCM. The effect of ECCM on islet insulin content was blocked with an inhibitory anti-HGF antibody. The HGF receptor was not different between control and IUGR islets, but VEGFA was lower and the high-affinity VEGF receptor was higher in IUGR islets and ECs, respectively. These findings show that paracrine actions from ECs increase islet insulin content, and in IUGR ECs, secretion of HGF was diminished. Given the potential feed-forward regulation of β-cell VEGFA and islet EC HGF, these two growth factors are highly integrated in normal pancreatic islet development, and this regulation is decreased in IUGR fetuses, resulting in lower pancreatic islet insulin concentrations and insulin secretion.
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO Perinatal Research Center, University of Colorado School of Medicine, Aurora, CO paul.rozance@ucdenver.edu.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Rozance
authors.affiliation: School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ.
authors.forename: Miranda
authors.initials: M
authors.lastname: Anderson
authors.affiliation: School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ.
authors.forename: Marina
authors.initials: M
authors.lastname: Martinez
authors.affiliation: School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ.
authors.forename: Anna
authors.initials: A
authors.lastname: Fahy
authors.affiliation: School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ.
authors.forename: Antoni R
authors.initials: AR
authors.lastname: Macko
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO Perinatal Research Center, University of Colorado School of Medicine, Aurora, CO.
authors.forename: Jenai
authors.initials: J
authors.lastname: Kailey
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO Pediatric Heart Lung Center, University of Colorado School of Medicine, Aurora, CO.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Seedorf
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO Pediatric Heart Lung Center, University of Colorado School of Medicine, Aurora, CO.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Abman
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO Pediatric Heart Lung Center, University of Colorado School of Medicine, Aurora, CO.
authors.forename: William W
authors.initials: WW
authors.lastname: Hay
authors.affiliation: School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ.
authors.forename: Sean W
authors.initials: SW
authors.lastname: Limesand
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000502:physiology; D005260:Female; D005317:Fetal Growth Retardation; D005333:Fetus / Q000502:physiology*; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D007515:Islets of Langerhans / Q000166:cytology*; D010179:Pancreas / Q000098:blood supply*; D010927:Placental Insufficiency / Q000662:veterinary*; D011247:Pregnancy; D012756:Sheep / Q000196:embryology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D017228:Hepatocyte Growth Factor