Circulation research · 2009
Insulin-like growth factor binding protein-3 mediates vascular repair by enhancing nitric oxide generation.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Kielczewski Jennifer L, Jarajapu Yagna P R, McFarland Evan L, Cai Jun, Afzal Aqeela, Li Calzi Sergio, Chang Kyung Hee, Lydic Todd, Shaw Lynn C, Busik Julia, Hughes Jeffrey, Cardounel Arturo J, Wilson Kenneth, Lyons Timothy J, Boulton Michael E, Mames Robert N, Chan-Ling Tailoi, Grant Maria B
Аннотация
RATIONALE: 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.
METHODS AND 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.
CONCLUSION: These studies support consideration of IGFBP-3 as a novel agent to restore the function of injured vasculature and restore NO generation.
OBJECTIVE: To examine the mechanism of IGFBP-3-mediated repair following vascular injury.
METHODS AND 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.
CONCLUSION: These studies support consideration of IGFBP-3 as a novel agent to restore the function of injured vasculature and restore NO generation.
Предметные рубрики MeSH
AnimalsAnimals, NewbornAstrocytesCell Adhesion MoleculesCell DeathCell MovementCell ProliferationCells, CulturedCeramidesCerebral ArteriesCytoprotectionDisease Models, AnimalEndothelial CellsFemaleGene Transfer TechniquesGreen Fluorescent ProteinsHumansInfant, NewbornInsulin-Like Growth Factor Binding Protein 3MaleMesenteric ArteriesMiceMice, Inbred C57BLMice, TransgenicMicrofilament ProteinsNitric OxideNitric Oxide Synthase Type IIIPhosphatidylinositol 3-KinasesPhosphoproteinsPregnancyProto-Oncogene Proteins c-aktRatsRats, Sprague-DawleyRetinal NeovascularizationRetinal VesselsRetinopathy of PrematurityScavenger Receptors, Class BSignal TransductionSphingomyelinsStem CellsVasodilationVasodilator-Stimulated Phosphoprotein