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Nan Gao, XiaoWei Liu, Chen Dong, Fushin X Yu; CXCL10 Suppression of hem- and lymph-angiogenesis in infected or inflamed B6 mouse corneas. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3232.
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This study sought to delineate the mechanisms by which CXCL10, a high inducible chemokine in corneal epithelial cells, acts as an intrinsic inhibitor for both hem- and lymph-angiogenesis in the infected or inflammatory corneas.
The expression of CXCL10 in Candida albicans-infected or sutured B6 mouse corneas were mediated by AAV-CXCL10 or antibody neutralization. Neovascularization in these infected or inflammatory corneas was monitored by slit lamp microscopy and corneal whole mount stained with CD31 for hem-vessels and LYVE-1 for lymphatic vessels. The expression of angiogenic factors were assessed with Proteome Profiler analysis, real-time PCR, and western blotting. The ability of CXCL10 to inhibit angiogenesis was also tested in vitro using Matrigel endothelial tube formation assay. The effect of CXCL10 on corneal angiogenesis was also assessed using post-infection topical application of CXCL10 as eye drops.
In normal eyes, blood and lymph-vessels can only be seen in the limbal region. In infected corneas, thick vessels were formed along with parallel lymph-vessel and numerous new vessels grew into the corneas with some free endings. While similar pattern of neovascularization can be seen in AAV9-GFP transfected cornea, there was no new vessel formation in AAV9-CXCL10 transfected or CXCL10 injected cornea. On the other hand, neutralization of CXCL10 resulted in much robust new vessel formations in both the numbers of new blood and lymphatic vessels and in length of the vessels. The expression of multiple angiogenic factors were affected by the levels of CXCL10 in infected corneas. In the suture model, overexpression of CXCL10 in CECs suppressed robust neovascularization of both hem- and lymph-vessels towards the sites of suture placements while individual CD31 positive cells can be found in sutured cornea. In vitro, the conditioned media from CXCL10 expressing human CECs induced the collapse of tube like networks formed by human brain blood vessel and lymphatic endothelial cells. Eye drops containing CXCL10 protected the cornea from neovascularization and preserved subbasal nerve plexus in infected corneas.
CXCL10 may be developed into an anti-angiogenic therapeutic to treat abnormal angiogenesis and topical CXCL10 may reduce the rate of rejection of corneal grafts by inhibiting lymph-vessel formation, especially for high risk fungal keratitis patients.
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