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Jingtai Cao, Yang Liu, Natasha Tirko, Weihong Xiao, Nicholas Papadopoulos, John S. Rudge, Christopher Daly, George D. Yancopoulos, Stanley J. Wiegand; Neutralization of Angiopoietin-2 Inhibits Ocular Angiogenesis and Vascular Leak, and Promotes Regression of Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1799.
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© ARVO (1962-2015); The Authors (2016-present)
To evaluate the role of angiopoietin-2 (Ang2) in corneal angiogenesis, vascular leak and inflammation following injury, and the effects of pharmacological neutralization of Ang2 on established choroidal neovascularization (CNV) in mice.
Corneal angiogenesis was induced by intrastromal placement of nylon sutures in C57Bl/6 mice. A fully human Ang2 antibody, that also binds and neutralizes murine Ang2, (25mg/kg) or the Fc portion of human IgG (hFc, 10mg/kg) was injected subcutaneously (SC) on days 0, 3 and 6 following injury. Corneal vasculature was labeled by intravenous injection of FITC-conjugated lectin on day 9 after injury, and the extent of NV was evaluated in corneal flatmounts. Lymphatic vessels were co-localized in the same specimens by LYVE-1 immunostaining. Macrophage infiltration was evaluated in cross-sections stained with rat anti-mouse F4/80 monoclonal antibody. For choroidal angiogenesis, CNV was induced by subretinal injection of a 75% matrigel solution (0.5 µl) in adult 129S1/SvlmJ mice. By 34 days after injection, choroidal neovessels were present in the matrigel and subretinal space. Anti-Ang2 (25mg/kg, SC) or hFc (10mg/kg, SC) was injected on days 34, 37 and 40. The vasculature was labeled by perfusion of a DiI solution on day 42. CNV volume was quantified in serial cryo-sections.
Corneal NV, vascular leakage, and growth of lymphatic vessels into the injured cornea were significantly decreased by anti-Ang2 treatment, compared to controls treated with hFc. In the CNV study, choroidal neovessels were present in the matrigel deposit and subretinal space in all untreated animals 34 days after injection of matrigel. On day 42, CNV volume in hFc treated controls was 72.5% greater than the day 34 CNV baseline, while treatment with anti-Ang2 resulted in a decrease of 36.3% in CNV volume (p <0.05). Anti-Ang2 treatment also significantly reduced CNV vessel density by 63.3% from the baseline (p <0.05).
Ang2 plays an important role in promoting the development of neovascularization, lymphangiogenesis and vascular leakage following corneal injury. Pharmacological inhibition of Ang2 not only blocked further development of CNV stimulated by subretinal deposition of matrigel, but also promoted the regression of recently formed CNV.
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