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M. M. Le Goff, M. Sutton, M. Slevin, M. J. Humphries, P. N. Bishop; Opticin Inhibits Preretinal Neovascularisation by Disrupting Pro-Angiogenic Signalling by Collagen. Invest. Ophthalmol. Vis. Sci. 2008;49(13):520. doi: https://doi.org/.
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Opticin is a glycoprotein that associates with the collagen fibrils of the vitreous. In pathological angiogenesis e.g. proliferative diabetic retinopathy, newly formed blood vessels use the cortical vitreous collagen as a substrate for growth/progression into the vitreous cavity. Using the mouse oxygen-induced retinopathy model we have previously demonstrated that opticin inhibits preretinal neovascularisation in a concentration-dependent manner. Therefore, opticin may inhibit pro-angiogenic signals from vitreous collagen fibrils.
Vascular networks were formed in 3D collagen gels by various endothelial cell (EC) types under FGF-2 stimulation in absence or presence of opticin. EC spreading assays on either immobilised collagen with opticin being added after the ECs had spread or directly on opticin in presence of various cations and anti-integrin antibodies were performed. The ECs were labelled with rhodamine-phalloidin or antibodies against opticin and vinculin.
In vitro studies revealed that opticin inhibits EC capillary morphogenesis in 3D collagen matrices. When added in solution, opticin disrupted collagen-induced EC spreading and it co-localised with α2β1 integrin clusters at the focal adhesions prior to their disassembly and subsequent disorganisation of the actin stress fiber network. Cell spreading assays revealed that opticin supported EC spreading in a cation and α2β1 integrin-dependent manner. Further cell spreading assays revealed that opticin interacts with ECs via the A-domain of the α2 integrin domain and that the binding sites for opticin and collagen to this domain largely overlap.
These results suggest that opticin inhibits collagen-driven capillary morphogenesis in its early stages through an α2β1 integrin-mediated mechanism. Therefore, opticin may act as a negative regulator of the pro-angiogenic signalling of collagen and hence, protect against preretinal neovascularisation.
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