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Vascular adhesion protein-1 blockade suppresses choroidal neovascularization

Kousuke Noda^*,,1, Haicheng She^*,,1, Toru Nakazawa^*,,1, Toshio Hisatomi^*,, Shintaro Nakao^*,, Lama Almulki^*,, Souska Zandi^*,, Shinsuke Miyahara^*,, Yasuhiro Ito^*,, Kennard L. Thomas^*,, Rebecca C. Garland^*,, Joan W. Miller^*,, Evangelos S. Gragoudas^*,, Yukihiko Mashima and Ali Hafezi-Moghadam^*,,2

^* Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA;

Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA; and

R-tech Ueno, Ltd., Tokyo, Japan

²Correspondence: Angiogenesis Laboratory, 325 Cambridge St., 3rd Floor, Boston, MA 02114, USA. E-mail: Ali_Hafezi-Moghadam{at}meei.harvard.edu

Vascular adhesion protein-1 (VAP-1) is an endothelial cell adhesion molecule involved in leukocyte recruitment. Leukocytes and, in particular, macrophages play an important role in the development of choroidal neovascularization (CNV), an integral component of age-related macular degeneration (AMD). Previously, we showed a role for VAP-1 in ocular inflammation. Here, we investigate the expression of VAP-1 in the choroid and its role in CNV development. VAP-1 was expressed in the choroid, exclusively in the vessels, and colocalized in the vessels of the CNV lesions. VAP-1 blockade with a novel and specific inhibitor significantly decreased CNV size, fluorescent angiographic leakage, and the accumulation of macrophages in the CNV lesions. Furthermore, VAP-1 blockade significantly reduced the expression of inflammation-associated molecules such as tumor necrosis factor (TNF) -, monocyte chemoattractant protein (MCP) -1, and intercellular adhesion molecule (ICAM) -1. This work provides evidence for an important role of VAP-1 in the recruitment of macrophages to CNV lesions, establishing a novel link between VAP-1 and angiogenesis. Inhibition of VAP-1 may become a new therapeutic strategy in the treatment of AMD.—Noda, K., She, H., Nakazawa, T., Hisatomi, T., Nakao, S., Almulki, L., Zandi, S., Miyahara, S., Ito, Y., Thomas, K. L., Garland, R. C., Miller, J. W., Gragoudas, E. S., Mashima, Y., Hafezi-Moghadam, A. Vascular adhesion protein-1 blockade suppresses choroidal neovascularization.

Key Words: age-related macular degeneration • leukocyte recruitment • macrophage • angiogenesis