June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Blockade of Vascular Endothelial Protein Tyrosine Phosphatase: A Novel Approach to Stabilizing the Retinal Vasculature
Author Affiliations & Notes
  • Ji-kui Shen
    Ophthalmology, Wimer Eye Institute, Baltimore, MD
  • Peter Campochiaro
    Ophthalmology, Wimer Eye Institute, Baltimore, MD
  • Christopher Seidel
    Ophthalmology, Wimer Eye Institute, Baltimore, MD
  • Aling Dong
    Ophthalmology, Wimer Eye Institute, Baltimore, MD
  • Maike Frye
    Department of Cell Biology, Max-Planck-Institute of Molecular Biomedicine, Muenster, Germany
  • Joseph McClung
    Department of Medicine, Division of Cardiology Duke University Medical Center Durham, Durham, NC
  • Sean Hackett
    Ophthalmology, Wimer Eye Institute, Baltimore, MD
  • Brian Howard
    Procter & Gamble, Cincinnati, OH
  • Dietmar Vestweber
    Department of Cell Biology, Max-Planck-Institute of Molecular Biomedicine, Muenster, Germany
  • Kevin Peters
    Aerpio Therapeutics, Cincinnati, OH
  • Footnotes
    Commercial Relationships Ji-kui Shen, None; Peter Campochiaro, Advance Cell Technology (C), Aerpio (C), Elan (C), Gene Signal (C), Genentech (C), GlaxoSmithKline (C), LPath, Inc (C), Norvox (C), Regeneron (C), Genentech (F), Genzyme (F), GlaxoSmithKline (F), Oxford Biomedica (F); Christopher Seidel, None; Aling Dong, None; Maike Frye, None; Joseph McClung, None; Sean Hackett, None; Brian Howard, Procter and Gamble (E); Dietmar Vestweber, None; Kevin Peters, Aerpio Therapeutics (I), Aerpio Therapeutics (E), Aerpio Therapeutics (P), Aerpio Therapeutics (S)
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 6094. doi:
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      Ji-kui Shen, Peter Campochiaro, Christopher Seidel, Aling Dong, Maike Frye, Joseph McClung, Sean Hackett, Brian Howard, Dietmar Vestweber, Kevin Peters; Blockade of Vascular Endothelial Protein Tyrosine Phosphatase: A Novel Approach to Stabilizing the Retinal Vasculature. Invest. Ophthalmol. Vis. Sci. 2013;54(15):6094.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: Emerging evidence indicates that activation of the angiopoietin (Ang)/Tie2 pathway promotes retinal and choroidal vascular stabilization; however development of a therapeutic approach to Tie2 activation for retinal/choroidal disease has been elusive. Vascular endothelial-protein tyrosine phosphatase (VE-PTP) is an important negative regulator of Tie2 activation. In this study the bioactivity of AKB-9778, a potent and selective small molecule inhibitor of VE-PTP, was assessed.

Methods: Tie2 phosphorylation was measured by immunoprecipitation in vitro and immunohistochemistry or immunoblots in vivo. The effect of intraocular or systemic AKB-9778 was tested in several models of ocular NV or leakage.

Results: VE-PTP was upregulated in hypoxic vascular endothelial cells in vitro and in vivo, and was strongly expressed in association with retinal NV. In cultured endothelial cells, AKB-9778 promoted phosphorylation of Tie2, enhanced angiopoietin (Ang)-1-induced Tie2 phosphorylation, and stimulated phosphorylation of signaling molecules in the Tie2 pathway including Akt, eNOS and ERK. AKB-9778 also induced phosphorylation of Tie2 in vivo and strongly suppressed subretinal or retinal NV. Increased expression of Ang-2 stimulated retinal NV, but strongly suppressed it when combined with AKB-9778. In addition to suppressing NV, AKB-9778 blocked VEGF-induced leakage from dermal and retinal vessels and prevented severe leakage and exudative retinal detachment mediated by high expression of VEGF.

Conclusions: Inhibition of VE-PTP is a novel strategy for Tie2 activation to stabilize retinal and choroidal blood vessels and this approach has potential to provide benefits in patients with a wide variety of retinal and choroidal vascular diseases.

Keywords: 700 retinal neovascularization • 706 retinopathy of prematurity • 695 retinal degenerations: cell biology  
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