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B.R. Mwaikambo, F. Sennlaub, S. Chemtob, P. Hardy; Activation of CD36 Inhibits and Prevents Progression of Corneal Neovascularization . Invest. Ophthalmol. Vis. Sci. 2005;46(13):4502.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Corneal neovascularization (CNV) is a significant problem associated with many corneal diseases. Although the molecular mechanisms underlying CNV remain poorly defined, vascular endothelial growth factor (VEGF) seems to play an indispensable role. Moreover, CD36, a critical anti–angiogenic receptor for thrombospondin (TSP)–1 (an endogenous inhibitor of angiogenesis), has been demonstrated to play significant roles in modulating angiogenesis by transducing signals leading to apoptosis and vessel regression. CD36 is expressed by microvascular endothelial cells, and its ligands include oxidized phospholipids. Consequently, we investigated the ability of CD36 to inhibit CNV and prevent its progression in a model of inflammation–induced angiogenesis. Methods: C57BL/6 mice were subjected to a model of chemically (0.15 M NaOH) and mechanically induced CNV. Twenty–four hours after corneal injury, one group was treated with an FA6–152 CD36 blocking antibody (100 and 200 µg/mL) or an isotype matched control, whereas a second group received treatment with an oxidized phospholipid (POVPC) (50 and 100 µg/mL) or vehicle. To determine whether CD36 activation prevented progression of established angiogenesis, POVPC (150 µg/mL) or vehicle treatments were initiated 10 days following corneal injury. In all groups, treatments were administered topically three times daily for 7 days, and neovascularization was analyzed by CD31–immunostained corneal flatmounts. We also studied the molecular effects of POVPC (100 µg/mL) via RT–PCR by assessing the mRNA expression of CD36, TSP–1, and VEGF–A in mice treated with POVPC or vehicle three times daily for 2, 4, or 7 days. Results: Blocking CD36 activity via FA6–152 (200 µg/mL) treatment resulted in a 47% increase in CNV compared to vehicle (p < 0.01). Conversely, activating CD36 with POVPC inhibited CNV in a dose–dependent manner, with a substantial 78% decrease in vessel density at 100 µg/mL compared to vehicle (p < 0.001). Furthermore, vessel progression was significantly reduced by 50% in mice treated with POVPC 10 days after corneal injury versus vehicle (p < 0.05). Finally, RT–PCR analysis indicated that CD36 and TSP–1 were upregulated after 2 days of POVPC treatment, whereas VEGF–A mRNA levels were 50% lower in animals treated for 7 days with POVPC . Conclusions: CD36 inhibits CNV and prevents progression of established neovascularization in a model of CNV. This appears to involve suppression of VEGF gene expression.
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