Insulin-like growth factor binding protein-3 mediates vascular repair by enhancing nitric oxide generation.
BACKGROUND
Insulin-like growth factor binding protein (IGFBP)-3 modulates vascular development by regulating endothelial progenitor cell (EPC) behavior, specifically stimulating EPC cell migration. This study was undertaken to investigate the mechanism of IGFBP-3 effects on EPC function and how IGFBP-3 mediates cytoprotection following vascular injury.


OBJECTIVE
To examine the mechanism of IGFBP-3-mediated repair following vascular injury.


RESULTS
We used 2 complementary vascular injury models: laser occlusion of retinal vessels in adult green fluorescent protein (GFP) chimeric mice and oxygen-induced retinopathy in mouse pups. Intravitreal injection of IGFBP-3-expressing plasmid into lasered GFP chimeric mice stimulated homing of EPCs, whereas reversing ischemia induced increases in macrophage infiltration. IGFBP-3 also reduced the retinal ceramide/sphingomyelin ratio that was increased following laser injury. In the OIR model, IGFBP-3 prevented cell death of resident vascular endothelial cells and EPCs, while simultaneously increasing astrocytic ensheathment of vessels. For EPCs to orchestrate repair, these cells must migrate into ischemic tissue. This migratory ability is mediated, in part, by endogenous NO generation. Thus, we asked whether the migratory effects of IGFBP-3 were attributable to stimulation of NO generation. IGFBP-3 increased endothelial NO synthase expression in human EPCs leading to NO generation. IGFBP-3 exposure also led to the redistribution of vasodilator-stimulated phosphoprotein, an NO regulated protein critical for cell migration. IGFBP-3-mediated NO generation required high-density lipoprotein receptor activation and stimulation of phosphatidylinositol 3-kinase/Akt pathway.


CONCLUSIONS
These studies support consideration of IGFBP-3 as a novel agent to restore the function of injured vasculature and restore NO generation.
Kielczewski
Jennifer L
JL
Program in Stem Cell Biology and Regenerative Medicine, University of Florida, Gainesville, FL 32610, USA.
Jarajapu
Yagna P R
YP
McFarland
Evan L
EL
Cai
Jun
J
Afzal
Aqeela
A
Li Calzi
Sergio
S
Chang
Kyung Hee
KH
Lydic
Todd
T
Shaw
Lynn C
LC
Busik
Julia
J
Hughes
Jeffrey
J
Cardounel
Arturo J
AJ
Wilson
Kenneth
K
Lyons
Timothy J
TJ
Boulton
Michael E
ME
Mames
Robert N
RN
Chan-Ling
Tailoi
T
Grant
Maria B
MB
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D016923:Cell Death; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D002536:Cerebral Arteries / Q000378:metabolism / Q000503:physiopathology; D019610:Cytoprotection; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015861:Retinal Neovascularization / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012171:Retinal Vessels / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012178:Retinopathy of Prematurity / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051122:Scavenger Receptors, Class B / Q000378:metabolism; D015398:Signal Transduction; D013109:Sphingomyelins / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D014664:Vasodilation; D000098662:Vasodilator-Stimulated Phosphoprotein
D015815:Cell Adhesion Molecules; D002518:Ceramides; D018972:Insulin-Like Growth Factor Binding Protein 3; D008840:Microfilament Proteins; D010750:Phosphoproteins; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D013109:Sphingomyelins; D000098662:Vasodilator-Stimulated Phosphoprotein; D049452:Green Fluorescent Proteins; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt