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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • October 2014

Published In

Volume / Issue

  • 124 / 10

Start / End Page

  • 4564 - 4576

PubMed ID

  • 25180601

Pubmed Central ID

  • PMC4191011

Electronic International Standard Serial Number (EISSN)

  • 1558-8238

Digital Object Identifier (DOI)

  • 10.1172/JCI74527

Language

  • eng

Conference Location

  • United States