Free insulin-like growth factor binding protein-3 (IGFBP-3) reduces retinal vascular permeability in association with a reduction of acid sphingomyelinase (ASMase)

Jennifer L. Kielczewski, Sergio Li Calzi, Lynn C. Shaw, Jun Cai, Xiaoping Qi, Qing Ruan, Lin Wu, Li Liu, Ping Hu, Tailoi Chan-Ling, Robert N. Mames, Sue Firth, Robert C. Baxter, Patric Turowski, Julia V. Busik, Michael E. Boulton, Maria B. Grant

Research output: Contribution to journalArticle

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Abstract

Purpose. To examine the effect of free insulin-like growth factor (IGF) binding protein-3 (IGFBP-3), independent of the effect of insulin-like growth factors, in modulating retinal vascular permeability. Methods. We assessed the ability of a form of IGFBP-3 that does not bind IGF-1 (IGFBP-3NB), to regulate the blood retinal barrier (BRB) using two distinct experimental mouse models, laser-induced retinal vessel injury and vascular endothelial growth factor (VEGF)-induced retinal vascular permeability. Additionally, in vitro studies were conducted. In the animal models, BRB permeability was quantified by intravenous injection of fluorescein labeled serum albumin followed by digital confocal image analysis of retinal flat-mounts. Claudin-5 and vascular endothelial-cadherin (VE-cadherin) localization at interendothelial junctions was studied by immunofluorescence. In vitro changes in transendothelial electrical resistance (TEER) and flux of fluorescent dextran in bovine retinal endothelial monolayers (BREC) were measured after IGFBP-3NB treatment. Acid (ASMase) and neutral (NSMase) sphingomyelinase mRNA levels and activity were measured in mouse retinas. Results. Four days postinjury, laser-injured mouse retinas injected with IGFBP-3NB plasmid demonstrated reduced vascular permeability compared with retinas of laser-injured mouse retinas injected with control plasmid. IGFBP-3NB administration resulted in a significant decrease in laser injury-associated increases in ASMase and NSMase mRNA and activity when compared with laser alone treated mice. In vivo, intravitreal injection of IGFBP-3NB reduced vascular leakage associated with intravitreal VEGF injection. IGFBP-3NB partially restored VEGF-induced in vivo permeability and dissociation of claudin-5 and VE-cadherin at junctional complexes. When IGFBP-3NB was applied basally to bovine retinal endothelial cells (BREC) in vitro, TEER increased and macromolecular flux decreased. Conclusions. Intravitreal administration of IGFBP-3NB preserves junctional integrity in the presence of VEGF or laser injury by reducing BRB permeability in part by modulating sphingomyelinase levels.

Original languageEnglish (US)
Pages (from-to)8278-8286
Number of pages9
JournalInvestigative Ophthalmology and Visual Science
Volume52
Issue number11
DOIs
StatePublished - Oct 2011
Externally publishedYes

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Sphingomyelin Phosphodiesterase
Retinal Vessels
Insulin-Like Growth Factor Binding Protein 3
Capillary Permeability
Insulin-Like Growth Factor I
Acids
Lasers
Blood-Retinal Barrier
Vascular Endothelial Growth Factor A
Retina
Claudin-5
Permeability
Somatomedins
Electric Impedance
Wounds and Injuries
Plasmids
Endothelial Cells
Messenger RNA
Intravitreal Injections
Dextrans

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

Free insulin-like growth factor binding protein-3 (IGFBP-3) reduces retinal vascular permeability in association with a reduction of acid sphingomyelinase (ASMase). / Kielczewski, Jennifer L.; Li Calzi, Sergio; Shaw, Lynn C.; Cai, Jun; Qi, Xiaoping; Ruan, Qing; Wu, Lin; Liu, Li; Hu, Ping; Chan-Ling, Tailoi; Mames, Robert N.; Firth, Sue; Baxter, Robert C.; Turowski, Patric; Busik, Julia V.; Boulton, Michael E.; Grant, Maria B.

In: Investigative Ophthalmology and Visual Science, Vol. 52, No. 11, 10.2011, p. 8278-8286.

Research output: Contribution to journalArticle

Kielczewski, JL, Li Calzi, S, Shaw, LC, Cai, J, Qi, X, Ruan, Q, Wu, L, Liu, L, Hu, P, Chan-Ling, T, Mames, RN, Firth, S, Baxter, RC, Turowski, P, Busik, JV, Boulton, ME & Grant, MB 2011, 'Free insulin-like growth factor binding protein-3 (IGFBP-3) reduces retinal vascular permeability in association with a reduction of acid sphingomyelinase (ASMase)', Investigative Ophthalmology and Visual Science, vol. 52, no. 11, pp. 8278-8286. https://doi.org/10.1167/iovs.11-8167
Kielczewski, Jennifer L. ; Li Calzi, Sergio ; Shaw, Lynn C. ; Cai, Jun ; Qi, Xiaoping ; Ruan, Qing ; Wu, Lin ; Liu, Li ; Hu, Ping ; Chan-Ling, Tailoi ; Mames, Robert N. ; Firth, Sue ; Baxter, Robert C. ; Turowski, Patric ; Busik, Julia V. ; Boulton, Michael E. ; Grant, Maria B. / Free insulin-like growth factor binding protein-3 (IGFBP-3) reduces retinal vascular permeability in association with a reduction of acid sphingomyelinase (ASMase). In: Investigative Ophthalmology and Visual Science. 2011 ; Vol. 52, No. 11. pp. 8278-8286.
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abstract = "Purpose. To examine the effect of free insulin-like growth factor (IGF) binding protein-3 (IGFBP-3), independent of the effect of insulin-like growth factors, in modulating retinal vascular permeability. Methods. We assessed the ability of a form of IGFBP-3 that does not bind IGF-1 (IGFBP-3NB), to regulate the blood retinal barrier (BRB) using two distinct experimental mouse models, laser-induced retinal vessel injury and vascular endothelial growth factor (VEGF)-induced retinal vascular permeability. Additionally, in vitro studies were conducted. In the animal models, BRB permeability was quantified by intravenous injection of fluorescein labeled serum albumin followed by digital confocal image analysis of retinal flat-mounts. Claudin-5 and vascular endothelial-cadherin (VE-cadherin) localization at interendothelial junctions was studied by immunofluorescence. In vitro changes in transendothelial electrical resistance (TEER) and flux of fluorescent dextran in bovine retinal endothelial monolayers (BREC) were measured after IGFBP-3NB treatment. Acid (ASMase) and neutral (NSMase) sphingomyelinase mRNA levels and activity were measured in mouse retinas. Results. Four days postinjury, laser-injured mouse retinas injected with IGFBP-3NB plasmid demonstrated reduced vascular permeability compared with retinas of laser-injured mouse retinas injected with control plasmid. IGFBP-3NB administration resulted in a significant decrease in laser injury-associated increases in ASMase and NSMase mRNA and activity when compared with laser alone treated mice. In vivo, intravitreal injection of IGFBP-3NB reduced vascular leakage associated with intravitreal VEGF injection. IGFBP-3NB partially restored VEGF-induced in vivo permeability and dissociation of claudin-5 and VE-cadherin at junctional complexes. When IGFBP-3NB was applied basally to bovine retinal endothelial cells (BREC) in vitro, TEER increased and macromolecular flux decreased. Conclusions. Intravitreal administration of IGFBP-3NB preserves junctional integrity in the presence of VEGF or laser injury by reducing BRB permeability in part by modulating sphingomyelinase levels.",
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T1 - Free insulin-like growth factor binding protein-3 (IGFBP-3) reduces retinal vascular permeability in association with a reduction of acid sphingomyelinase (ASMase)

AU - Kielczewski, Jennifer L.

AU - Li Calzi, Sergio

AU - Shaw, Lynn C.

AU - Cai, Jun

AU - Qi, Xiaoping

AU - Ruan, Qing

AU - Wu, Lin

AU - Liu, Li

AU - Hu, Ping

AU - Chan-Ling, Tailoi

AU - Mames, Robert N.

AU - Firth, Sue

AU - Baxter, Robert C.

AU - Turowski, Patric

AU - Busik, Julia V.

AU - Boulton, Michael E.

AU - Grant, Maria B.

PY - 2011/10

Y1 - 2011/10

N2 - Purpose. To examine the effect of free insulin-like growth factor (IGF) binding protein-3 (IGFBP-3), independent of the effect of insulin-like growth factors, in modulating retinal vascular permeability. Methods. We assessed the ability of a form of IGFBP-3 that does not bind IGF-1 (IGFBP-3NB), to regulate the blood retinal barrier (BRB) using two distinct experimental mouse models, laser-induced retinal vessel injury and vascular endothelial growth factor (VEGF)-induced retinal vascular permeability. Additionally, in vitro studies were conducted. In the animal models, BRB permeability was quantified by intravenous injection of fluorescein labeled serum albumin followed by digital confocal image analysis of retinal flat-mounts. Claudin-5 and vascular endothelial-cadherin (VE-cadherin) localization at interendothelial junctions was studied by immunofluorescence. In vitro changes in transendothelial electrical resistance (TEER) and flux of fluorescent dextran in bovine retinal endothelial monolayers (BREC) were measured after IGFBP-3NB treatment. Acid (ASMase) and neutral (NSMase) sphingomyelinase mRNA levels and activity were measured in mouse retinas. Results. Four days postinjury, laser-injured mouse retinas injected with IGFBP-3NB plasmid demonstrated reduced vascular permeability compared with retinas of laser-injured mouse retinas injected with control plasmid. IGFBP-3NB administration resulted in a significant decrease in laser injury-associated increases in ASMase and NSMase mRNA and activity when compared with laser alone treated mice. In vivo, intravitreal injection of IGFBP-3NB reduced vascular leakage associated with intravitreal VEGF injection. IGFBP-3NB partially restored VEGF-induced in vivo permeability and dissociation of claudin-5 and VE-cadherin at junctional complexes. When IGFBP-3NB was applied basally to bovine retinal endothelial cells (BREC) in vitro, TEER increased and macromolecular flux decreased. Conclusions. Intravitreal administration of IGFBP-3NB preserves junctional integrity in the presence of VEGF or laser injury by reducing BRB permeability in part by modulating sphingomyelinase levels.

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