Placental insufficiency decreases pancreatic vascularity and disrupts hepatocyte growth factor signaling in the pancreatic islet endothelial cell in fetal sheep

Paul J. Rozance, Miranda Anderson, Marina Martinez, Anna Fahy, Antoni R. Macko, Jenai Kailey, Gregory J. Seedorf, Steven H. Abman, William W. Hay, Sean W Limesand

Research output: Contribution to journalArticle

28 Citations (Scopus)

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 feedforward 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.

Original languageEnglish (US)
Pages (from-to)555-564
Number of pages10
JournalDiabetes
Volume64
Issue number2
DOIs
StatePublished - Feb 1 2015

Fingerprint

Placental Insufficiency
Hepatocyte Growth Factor
Islets of Langerhans
Sheep
Endothelial Cells
Conditioned Culture Medium
Growth
Insulin
Vascular Endothelial Growth Factor A
Paracrine Communication
Proto-Oncogene Proteins c-met
Vascular Endothelial Growth Factor Receptor
Pancreas
Intercellular Signaling Peptides and Proteins
Fetus
Communication
Hormones
Antibodies

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Placental insufficiency decreases pancreatic vascularity and disrupts hepatocyte growth factor signaling in the pancreatic islet endothelial cell in fetal sheep. / Rozance, Paul J.; Anderson, Miranda; Martinez, Marina; Fahy, Anna; Macko, Antoni R.; Kailey, Jenai; Seedorf, Gregory J.; Abman, Steven H.; Hay, William W.; Limesand, Sean W.

In: Diabetes, Vol. 64, No. 2, 01.02.2015, p. 555-564.

Research output: Contribution to journalArticle

Rozance, Paul J. ; Anderson, Miranda ; Martinez, Marina ; Fahy, Anna ; Macko, Antoni R. ; Kailey, Jenai ; Seedorf, Gregory J. ; Abman, Steven H. ; Hay, William W. ; Limesand, Sean W. / Placental insufficiency decreases pancreatic vascularity and disrupts hepatocyte growth factor signaling in the pancreatic islet endothelial cell in fetal sheep. In: Diabetes. 2015 ; Vol. 64, No. 2. pp. 555-564.
@article{924156d72b3b43e0822950e26149225a,
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 feedforward 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.",
author = "Rozance, {Paul J.} and Miranda Anderson and Marina Martinez and Anna Fahy and Macko, {Antoni R.} and Jenai Kailey and Seedorf, {Gregory J.} and Abman, {Steven H.} and Hay, {William W.} and Limesand, {Sean W}",
year = "2015",
month = "2",
day = "1",
doi = "10.2337/db14-0462",
language = "English (US)",
volume = "64",
pages = "555--564",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "2",

}

TY - JOUR

T1 - Placental insufficiency decreases pancreatic vascularity and disrupts hepatocyte growth factor signaling in the pancreatic islet endothelial cell in fetal sheep

AU - Rozance, Paul J.

AU - Anderson, Miranda

AU - Martinez, Marina

AU - Fahy, Anna

AU - Macko, Antoni R.

AU - Kailey, Jenai

AU - Seedorf, Gregory J.

AU - Abman, Steven H.

AU - Hay, William W.

AU - Limesand, Sean W

PY - 2015/2/1

Y1 - 2015/2/1

N2 - 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 feedforward 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.

AB - 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 feedforward 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.

UR - http://www.scopus.com/inward/record.url?scp=84921903935&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84921903935&partnerID=8YFLogxK

U2 - 10.2337/db14-0462

DO - 10.2337/db14-0462

M3 - Article

C2 - 25249573

AN - SCOPUS:84921903935

VL - 64

SP - 555

EP - 564

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 2

ER -