Journal
LABORATORY INVESTIGATION
Volume 96, Issue 11, Pages 1178-1188Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/labinvest.2016.99
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Funding
- Japan Society for the Promotion of Science [15H04995, 26293374, 26670757, 15J03433]
- Grants-in-Aid for Scientific Research [26293374, 15J03433, 15H04995] Funding Source: KAKEN
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Tenascin-C is expressed in choroidal neovascular (CNV) membranes in eyes with age-related macular degeneration (AMD). However, its role in the pathogenesis of CNV remains to be elucidated. Here we investigated the role of tenascin-C in CNV formation. In immunofluorescence analyses, tenascin-C co-stained with alpha-SMA, pan-cytokeratin, CD31, CD34, and integrin alpha(V) in the CNV membranes of patients with AMD and a mouse model of laser-induced CNV. A marked increase in the expression of tenascin-C mRNA and protein was observed 3 days after laser photocoagulation in the mouse CNV model. Tenascin-C was also shown to promote proliferation and inhibit adhesion of human retinal pigment epithelial (hRPE) cells in vitro. Moreover, tenascin-C promoted proliferation, adhesion, migration, and tube formation in human microvascular endothelial cells (HMVECs); these functions were, however, blocked by cilengitide, an integrin alpha(V) inhibitor. Exposure to TGF-beta 2 increased tenascin-C expression in hRPE cells. Conditioned media harvested from TGF-beta 2-treated hRPE cell cultures enhanced HMVEC proliferation and tube formation, which were inhibited by pretreatment with tenascin-C siRNA. The CNV volume was significantly reduced in tenascin-C knockout mice and tenascin-C siRNA-injected mice. These findings suggest that tenascin-C is secreted by transdifferentiated RPE cells and promotes the development of CNV via integrin aV in a paracrine manner. Therefore, tenascin-C could be a potential therapeutic target for the inhibition of CNV development associated with AMD.
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