title: 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.forename: Jikui
authors.initials: J
authors.lastname: Shen
authors.forename: Maike
authors.initials: M
authors.lastname: Frye
authors.forename: Bonnie L
authors.initials: BL
authors.lastname: Lee
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Reinardy
authors.forename: Joseph M
authors.initials: JM
authors.lastname: McClung
authors.forename: Kun
authors.initials: K
authors.lastname: Ding
authors.forename: Masashi
authors.initials: M
authors.lastname: Kojima
authors.forename: Huiming
authors.initials: H
authors.lastname: Xia
authors.forename: Christopher
authors.initials: C
authors.lastname: Seidel
authors.forename: Raquel
authors.initials: R
authors.lastname: Lima e Silva
authors.forename: Aling
authors.initials: A
authors.lastname: Dong
authors.forename: Sean F
authors.initials: SF
authors.lastname: Hackett
authors.forename: Jiangxia
authors.initials: J
authors.lastname: Wang
authors.forename: Brian W
authors.initials: BW
authors.lastname: Howard
authors.forename: Dietmar
authors.initials: D
authors.lastname: Vestweber
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Kontos
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Peters
authors.forename: Peter A
authors.initials: PA
authors.lastname: Campochiaro
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D002384:Catalysis; D015687:Cell Hypoxia; D002829:Choroid / Q000098:blood supply; D005123:Eye / Q000098:blood supply*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D000860:Hypoxia; D008268:Macular Degeneration; D051379:Mice; D008822:Mice, Transgenic; D010100:Oxygen / Q000378:metabolism; D010766:Phosphorylation; D042787:Receptor, TIE-2 / Q000378:metabolism*; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000378:metabolism*; D012171:Retinal Vessels / Q000473:pathology*; D015398:Signal Transduction; D013451:Sulfonic Acids / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C000598564:AKB-9778; D000814:Aniline Compounds; D013451:Sulfonic Acids; D042461:Vascular Endothelial Growth Factor A; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D010100:Oxygen