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J. Cao, Y. Liu, W. Xiao, N. Papadopoulos, J. S. Rudge, G. D. Yancopoulos, S. J. Wiegand; Neutralization of Angiopoietin-2 Inhibits Progression and Promotes Regression of Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3769. doi: https://doi.org/.
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Choroidal neovascularization (CNV) is a feature of several retinal diseases including the "wet" form of age-related macular degeneration (AMD). AMD is characterized by development of focal subretinal deposits (drusen), disruption of Bruch's membrane and degeneration of retinal pigment epithelium (RPE). Subretinal injection of matrigel can induce the formation of CNV in rodents (Zhao, et al. Molecular Vision 2007; 13:873). Angipoietin-2 (Ang2) is a ligand of the Tie2 receptor which is upregulated in many forms of pathological neovascularization. The present study evaluates the effects of pharmacological neutralization of Angiopoietin-2 (Ang2) on the development of CNV following sub-retinal injection of matrigel.
CNV was induced in adult, male, Sprague-Dawley rats by subretinal injection of a 75% matrigel solution (1.2 mcL). Ten days later, the extent of CNV was evaluated in one group of rats. The remaining animals received injections of an Ang2 neutralizing antibody (25mg/kg, SC) or a control protein (human Fc, 10mg/kg, SC) on days 10, 13 and 16 following matrigel injection. On day 20 the vasculature was labeled by perfusion of a DiI solution. The eyes were harvested and serial sections (50 mcm each) were cut on a cryostat through the area overlying the matrigel deposit, and examined by fluorescence microscopy. The CNV volume was quantified through serial sections of each eye using Photoshop CS2, Fovea 4.0, and Scion Image program. The area of CNV was measured (in mcm2) every third section, and an estimate of the total CNV volume was calculated. Alternate series of sections through the lesion were stained with hematoxylin, or with an antibody against rat CD45.
Numerous choroidal neovessels were present in the matrigel deposit and adjacent subretinal space 10 days after injection. On day 20, the CNV volume in animals treated with anti-Ang2 was 60% of CNV volume evident in untreated rats on day 10, representing a 40% reduction from the baseline. In contrast, the CNV volume was greater in Fc controls at day 20 than in untreated animals at day 10.
Pharmacological inhibition of Ang2 not only blocked further development of CNV, but also promoted the regression of recently formed CNV stimulated by subretinal deposition of matrigel. These findings demonstrate that endogenous Ang2 plays an important role in the development of choroidal neovascularization.
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