April 2010
Volume 51, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2010
Insulin-Like Growth Factor Binding Protein-3 (IGFBP-3) Provides Neurovascular Protection Through Scavenging Receptor-b1 (SRB1)-Dependent Nitric Oxide (NO) Release
Y. Yan; Y. P. R. Jarajapu; J. L. Kielczewski; E. McFarland; M. E. Boulton; R. C. Baxter; R. N. Mames; T. Chan-Ling; T. Gardiner; M. B. Grant
Author Affiliations & Notes
  • Y. Yan
    Pharmacology and Therapeutics, Anatomy,
    University of Florida, Gainesville, Florida
  • Y. P. R. Jarajapu
    Pharmacology and Therapeutics, Anatomy,
    University of Florida, Gainesville, Florida
  • J. L. Kielczewski
    Pharmacology and Therapeutics, Anatomy,
    University of Florida, Gainesville, Florida
  • E. McFarland
    Pharmacology and Therapeutics, Anatomy,
    University of Sydney, Sydney, Australia
  • M. E. Boulton
    Anatomy and Cell Biology, Medicine,
    University of Florida, Gainesville, Florida
  • R. C. Baxter
    Anatomy and Cell Biology, Medicine,
    University of Sydney, Sydney, Australia
  • R. N. Mames
    Affiliate UF, Retina Center, Gainesville, Florida
  • T. Chan-Ling
    Pharmacology and Therapeutics, Anatomy,
    University of Sydney, Sydney, Australia
  • T. Gardiner
    Ophthalmology and Vision, Queen's University, Belfast, Ireland
  • M. B. Grant
    Pharmacology and Therapeutics, Anatomy,
    University of Florida, Gainesville, Florida
  • Footnotes
    Commercial Relationships  Y. Yan, None; Y.P.R. Jarajapu, None; J.L. Kielczewski, None; E. McFarland, None; M.E. Boulton, None; R.C. Baxter, None; R.N. Mames, None; T. Chan-Ling, None; T. Gardiner, None; M.B. Grant, None.
  • Footnotes
    Support  NIH grants 2RO1 EY012601-08 , 2RO1 EY007739-17, R01 EY018358
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 4479. doi:
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      Y. Yan, Y. P. R. Jarajapu, J. L. Kielczewski, E. McFarland, M. E. Boulton, R. C. Baxter, R. N. Mames, T. Chan-Ling, T. Gardiner, M. B. Grant; Insulin-Like Growth Factor Binding Protein-3 (IGFBP-3) Provides Neurovascular Protection Through Scavenging Receptor-b1 (SRB1)-Dependent Nitric Oxide (NO) Release. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4479.

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Abstract

Purpose: : Vascular protective effect of IGFBP3 involves recruitment of endothelial progenitor cells (EPCs) to the areas of vascular injury and release of NO. In this study, we examined the neuroprotective effect of IGFBP3 in the oxygen-induced retinopathy (OIR) model and evaluated possible signaling pathways involved in NO release.

Methods: : Either control or IGFBP3-expressing plasmid was injected intravitreally in mouse pups on postnatal day (P) 1 before they underwent the OIR. Apoptotic cells were enumerated in the retina at P17 by TUNEL assay or electron microscopy. Vasodilatation to IGFBP3 was determined in rat posterior cerebral arteries (PCAs). Signaling pathways involved in activation of endothelial nitric oxide synthase (eNOS) by IGFBP3 were delineated in human microvascular or aortic endothelial cells (HMVECs or HAECs) by evaluating NO release, eNOS activity and phosphorylation of eNOS and akt. The effects of IGFBP3 mutants that cannot localize to the nucleus or that cannot bind to IGF-1 were also evaluated.

Results: : In the OIR model, IGFBP3 reduced the incidence of apoptosis in the neural retina (P<0.0007) compared to the control. Intraluminal IGFBP3 (100ng/ml) stimulated NO release and attenuated constriction to pressure in PCAs. In HMVECs or HAECs, IGFBP3 stimulated NO release, eNOS activity and phosphorylation of eNOS (ser1177) that were decreased by SRB1-antibody or LY294002 (PI3-kinase inhibitor) or triciribin (akt inhibitor) but not by PP2 (Src-kinase inhibitor). Akt (ser473 and thr308) phosphorylation by IGFBP3 was decreased by SRB1-antibody or LY294002. Mutants of IGFBP3 were equipotent to the wild type in stimulating NO release and eNOS activity and akt phosphorylation.

Conclusions: : These results suggest that the neurovascular protection by IGFBP3 likely involves enhanced perfusion of the retina by SRB1-dependent NO release via PI3-kinase/akt pathway.

Keywords: nitric oxide • neuroprotection • ischemia 
© 2010, The Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Permission to republish any abstract or part of an abstract in any form must be obtained in writing from the ARVO Office prior to publication.
Copyright © 2025 Association for Research in Vision and Ophthalmology.
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