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Chintala Hemabindu, Jin-ok Choi, Jincai Shan, Maria Grant, Brahim Chaqour; The Matricellular Protein CCN1 is Required for Growth, Maturation and Stabilization of the Retinal Vasculature. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5141. doi: https://doi.org/.
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The CCN1 protein also known as cysteine-rich protein 61 (Cyr61) is an inducible immediate-early gene-encoded extracellular matrix protein with critical functions during organ system development and in mediating inflammation, wound healing and repair in adult life. Our laboratory has previously found that the expression of CCN1 either directly via gene transfer or indirectly via cell transplantation in retina enhanced normal retinal vascularization and reduced pathological angiogenesis in the mouse model of oxygen-induced retinopathy. In this study, we used inducible gene targeting and transgenic expression approaches to study the regulation and functional significance of CCN1 expression in the retinal vasculature.
To examine the endogenous expression of CCN1 in the retina, CCN1 promoter-GFP reporter mice were generated and GFP tissue localization was analyzed by immunohistochemical methods of flat mounted retinas. Endothelial tissue-specific control of CCN1 gene deletion was carried out by crossing mice carrying floxed CCN1 alleles with mice with tamoxifen-activated Cdh5(PAC)-CreERT2. Using immunohistochemistry, retinal vascular changes were characterized at postnatal day (P) 4 and (P) 7 following tamoxifen injection.
CCN1 promoter-driven GFP, which recapitulates endogenous CCN1 levels in mice, showed a dynamic but transient expression of the transgene in the developing retinal vasculature. Endothelial cells primarily and pericytes and astrocytes were sources of CCN1. Endothelium-specific inactivation of the CCN1 gene caused retinal vascular malformations typical of faulty maturation and stabilization including reduced growth, defective branching, enlarged caliber of the vascularture and increased vascular leakage. Both endothelial and mural layers were affected as endothelial tip cell formation was reduced and astrocyte migration and pericyte recruitment were impaired.
Our studies support that precise temporal CCN1 expression is crucial for the formation, maturation and stabilization of retinal vessel during development
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