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K. Noda, H. She, T. Nakazawa, T. Hisatomi, S. Nakao, L. Almulki, J. W. Miller, E. S. Gragoudas, Y. Mashima, A. Hafezi-Moghadam; Vascular Adhesion Protein-1 Blockade Suppresses Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2008;49(13):539.
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© ARVO (1962-2015); The Authors (2016-present)
Vascular adhesion protein-1 (VAP-1), a 170-kDa homodimeric sialylated glycoprotein, is an endothelial adhesion molecule, involved in leukocyte recruitment. Macrophages play an important role in the development of choroidal neovascularization (CNV), an integral component of age-related macular degeneration (AMD). Recently, we showed the role of VAP-1 in ocular inflammation. Here, we investigate the expression of VAP-1 in the choroid and its role in CNV development.
Rats (8-12 weeks old) were treated in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. Immunohistochemistry and RT-PCR were performed to determine whether VAP-1 was expressed in the normal choroid. CNV was induced by laser photocoagulation (150mW, 100µm, 100msec). Animals received daily injections of the VAP-1 inhibitor, U-V002 (0.3mg/kg), or vehicle control. Seven days after laser injury, choroidal flat mounts were prepared and the size of the CNV lesions was quantified. Macrophage infiltration and the levels of inflammatory cytokines were assessed 3 days after laser injury.
In normal animals, VAP-1 expression in the choroid was exclusive to the vasculature. In laser-injured animals VAP-1 also co-localized with the new vessels of the CNV lesions. Seven days after laser injury, the animals treated with the VAP-1 inhibitor showed a significant decrease in CNV size (14,536±2,175µm2), compared with vehicle-treated controls (25,026±1,586µm2, p<0.01). The number of accumulated macrophages 3 days after laser injury was significantly reduced by 41% with blockade of VAP-1 compared to vehicle-treated controls (p<0.05). VAP-1 blockade significantly reduced the expression of inflammation-associated molecules such as tumor necrosis factor (TNF)-α (p<0.05), monocyte chemoattractant protein (MCP)-1 (p<0.01) and intercellular adhesion molecule (ICAM)-1 (p<0.01).
The current data indicate a role for VAP-1 in the recruitment of macrophages to CNV lesions. VAP-1 inhibition may become a novel therapeutic strategy in the treatment of ocular inflammatory diseases, such as AMD.
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