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Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature.

Publication ,  Journal Article
Shen, J; Frye, M; Lee, BL; Reinardy, JL; McClung, JM; Ding, K; Kojima, M; Xia, H; Seidel, C; Lima e Silva, R; Dong, A; Hackett, SF; Wang, J ...
Published in: J Clin Invest
October 2014

Retinal and choroidal neovascularization (NV) and vascular leakage contribute to visual impairment in several common ocular diseases. The angiopoietin/TIE2 (ANG/TIE2) pathway maintains vascular integrity, and negative regulators of this pathway are potential therapeutic targets for these diseases. Here, we demonstrated that vascular endothelial-protein tyrosine phosphatase (VE-PTP), which negatively regulates TIE2 activation, is upregulated in hypoxic vascular endothelial cells, particularly in retinal NV. Intraocular injection of an anti-VE-PTP antibody previously shown to activate TIE2 suppressed ocular NV. Furthermore, a small-molecule inhibitor of VE-PTP catalytic activity (AKB-9778) activated TIE2, enhanced ANG1-induced TIE2 activation, and stimulated phosphorylation of signaling molecules in the TIE2 pathway, including AKT, eNOS, and ERK. In mouse models of neovascular age-related macular degeneration, AKB-9778 induced phosphorylation of TIE2 and strongly suppressed NV. Ischemia-induced retinal NV, which is relevant to diabetic retinopathy, was accentuated by the induction of ANG2 but inhibited by AKB-9778, even in the presence of high levels of ANG2. AKB-9778 also blocked VEGF-induced leakage from dermal and retinal vessels and prevented exudative retinal detachments in double-transgenic mice with high expression of VEGF in photoreceptors. These data support targeting VE-PTP to stabilize retinal and choroidal blood vessels and suggest that this strategy has potential for patients with a wide variety of retinal and choroidal vascular diseases.

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Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

October 2014

Volume

124

Issue

10

Start / End Page

4564 / 4576

Location

United States

Related Subject Headings

  • Vascular Endothelial Growth Factor A
  • Sulfonic Acids
  • Signal Transduction
  • Retinal Vessels
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3
  • Receptor, TIE-2
  • Phosphorylation
  • Oxygen
  • Mice, Transgenic
  • Mice
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Shen, J., Frye, M., Lee, B. L., Reinardy, J. L., McClung, J. M., Ding, K., … Campochiaro, P. A. (2014). Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature. J Clin Invest, 124(10), 4564–4576. https://doi.org/10.1172/JCI74527
Shen, Jikui, Maike Frye, Bonnie L. Lee, Jessica L. Reinardy, Joseph M. McClung, Kun Ding, Masashi Kojima, et al. “Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature.J Clin Invest 124, no. 10 (October 2014): 4564–76. https://doi.org/10.1172/JCI74527.
Shen J, Frye M, Lee BL, Reinardy JL, McClung JM, Ding K, et al. Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature. J Clin Invest. 2014 Oct;124(10):4564–76.
Shen, Jikui, et al. “Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature.J Clin Invest, vol. 124, no. 10, Oct. 2014, pp. 4564–76. Pubmed, doi:10.1172/JCI74527.
Shen J, Frye M, Lee BL, Reinardy JL, McClung JM, Ding K, Kojima M, Xia H, Seidel C, Lima e Silva R, Dong A, Hackett SF, Wang J, Howard BW, Vestweber D, Kontos CD, Peters KG, Campochiaro PA. Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature. J Clin Invest. 2014 Oct;124(10):4564–4576.

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

October 2014

Volume

124

Issue

10

Start / End Page

4564 / 4576

Location

United States

Related Subject Headings

  • Vascular Endothelial Growth Factor A
  • Sulfonic Acids
  • Signal Transduction
  • Retinal Vessels
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3
  • Receptor, TIE-2
  • Phosphorylation
  • Oxygen
  • Mice, Transgenic
  • Mice