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Brahim Chaqour, Maria B. Grant, Hemabindu Chintala, Rahul Parmar, Moneka Kamalska; Differential Regulation of Retinal Neovascularization by the Modular Domains of The Matricellular Protein Cysteine-Rich 61 (CCN1/Cyr61). Invest. Ophthalmol. Vis. Sci. 2012;53(14):3004.
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The CCN1 protein also known as cysteine-rich protein 61 (Cyr61) is a dynamically expressed, matricellular protein required for proper angiogenesis and vasculogenesis during development. We have previously demonstrated that lentivirus-mediated expression of CCN1 in the mouse eye, promoted normalization of the retinal vasculature in the mouse model of oxygen-induced retinopathy (OIR). Structurally, the CCN1 protein is organized into 4 modular domains including IGFBP, vWF, TSP and CT domain. This multimodular organization is a means of generating through proteolytic cleavage, variants/bioactive domains that exhibit a diverse range of activities. This study examined the angiogenic potential of CCN1 and CCN1-truncated forms in the mouse OIR model.
Lentiviral vectors expressing either the full-length or serially-truncated forms of the CCN1 protein were prepared (i.e., lnv-CCN1: full-length; lnv-CCN11-3: CT truncated form; lnv-CCN11-2: CT and TSP-truncated form; lnv-CCN11: CT, TSP and vWF truncated form). Each vector was intravitreally injected in the eyes of mouse pups at postnatal day (P) 4. Mouse pups were then subjected to OIR and the retinas were analyzed for vaso-obliteration at P12 and neovascularization at P17.
Truncation of the CT domain through injection lnv-CCN11-3 had no effect on hyperoxia-induced vasoobliteration at P12, but the reduction of neovascular tufts at P17 was greater than those induced by the full-length protein, lnv-CCN1. Truncation of both the CT and TSP1 domains through injection lnv-CCN11-2, reduced avascular areas at P12 but significantly increased neovascular tuft formation at P17. Truncation of the CT, TSP-1 and vWF domains through injection lnv-CCN11 had no effects on hyperoxia-induced vasoobliteration but further reduced neovascular tuft formation in comparison with the full-length protein.
The presence of IGFBP and TSP domains inherently inhibits neovascular tuft formation while vWF and CT domains increase resistance to hyperoxia-induced vaso-obliteration.
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