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 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 4

AKB-9778 stimulates TIE2 phosphorylation in subretinal and retinal NV.

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AKB-9778 stimulates TIE2 phosphorylation in subretinal and retinal NV. (...
(A) At P21, Rho-VEGF–transgenic mice were given a s.c. injection of vehicle or 20 mg/kg AKB-9778, and after 12 hours, retinal flat mounts were immunohistochemically stained for TIE2 (red) and p-TIE2 (green). In vehicle control mice, new vessels stained for TIE2, but not p-TIE2, while in AKB-9778–treated mice, they stained for both TIE2 and p-TIE2. Scale bars: 100 μm. (B) At P16, mice with ischemic retinopathy were administered a s.c. injection of vehicle or 20 mg/kg AKB-9778 or an intraocular injection of 500 ng ANG1, and after 12 hours, retinas were double labeled for TIE2 (red) and p-TIE2 (green). Eyes of vehicle control mice showed extensive TIE2+ NV on the retinal surface that did not stain for p-TIE2, but in AKB-9778–treated mice, the TIE2+ NV also stained for p-TIE2. Scale bars: 100 μm. (C) Likewise, ischemia-induced retinal NV stained for both TIE2 and p-TIE2 after intraocular injection of 500 ng ANG1. Scale bars: 100 μm.