Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature
Jikui Shen, … , Kevin G. Peters, Peter A. Campochiaro
Jikui Shen, … , Kevin G. Peters, Peter A. Campochiaro
Published October 1, 2014; First published September 2, 2014
Citation Information: J Clin Invest. 2014;124(10):4564-4576. https://doi.org/10.1172/JCI74527.
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Research Article Vascular biology

Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature

Abstract

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

Authors

Jikui Shen, Maike Frye, Bonnie L. Lee, Jessica L. Reinardy, Joseph M. McClung, Kun Ding, Masashi Kojima, Huiming Xia, Christopher Seidel, Raquel Lima e Silva, Aling Dong, Sean F. Hackett, Jiangxia Wang, Brian W. Howard, Dietmar Vestweber, Christopher D. Kontos, Kevin G. Peters, Peter A. Campochiaro

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Figure 1

VE-PTP is upregulated in hypoxic endothelial cells and plays an important role in ocular NV.

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VE-PTP is upregulated in hypoxic endothelial cells and plays an importan...
(A) After incubation in 5% oxygen for 0, 4, or 16 hours, hypoxic HUVECs showed an increase in VE-PTP. (B) GSA lectin–stained retinal NV in P17 mice with ischemic retinopathy stained for VE-PTP, with faint staining of preexistent retinal vessels (arrowheads). Scale bar: 100 μm. (C) Elimination of primary antibody eliminated staining. Scale bar: 100 μm. (D) Nonischemic retinas at P17 showed normal GSA-stained vessels, no NV, and no VE-PTP staining. Scale bar: 100 μm. (E) At P12, mice with ischemic retinopathy were administered an intravitreous injection of 0.1, 0.5, or 2 μg anti–VE-PTP or 2 μg IgG isotype control (n ≥12 for each). At P17, there was extensive GSA-stained retinal NV in control IgG–injected eyes and significantly less detected in eyes injected with 2 μg anti–VE-PTP. *P < 0.001 for comparison with IgG control by 1-way ANOVA with Bonferroni’s correction. Scale bar: 500 μm. (F) At P15, Rho-VEGF–transgenic mice were given an intravitreous injection of 0.5 or 2 μg anti–VE-PTP in 1 eye and a corresponding dose of control IgG in the fellow eye (n = 6 for each). At P21, there was significantly less GSA-stained subretinal NV in eyes injected with 0.5 or 2 μg anti–VE-PTP than in control IgG–injected eyes. *P = 0.01 by unpaired t test for comparison with IgG control fellow eyes. Scale bar: 100 μm. (G) Intravitreous injection of 2 μg anti–VE-PTP significantly reduced the area of choroidal NV at Bruch’s membrane rupture sites compared with control IgG. *P < 0.001 by 1-way ANOVA with Bonferroni’s correction. Scale bar: 100 μm. MW, molecular weight.