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Barbara Maria Braunger, Sarah V Leimbeck, Anja Schlecht, Cornelia Volz, Herbert Jaegle, Ernst R Tamm; Deletion of ocular TGF-β signaling mimics essential characteristics of diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):63.
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© ARVO (1962-2015); The Authors (2016-present)
The vascular phenotypes of diabetic retinopathy are important causative or contributing factors of vision loss and blindness. However, its molecular causes are not sufficiently clear. To identify the role of TGF-β signaling for maintenance and proliferation of retinal vessels, we generated mice with a conditional deletion of the TGF-β type II (TβRII) receptor which is essential for TGF-β signaling.
Floxed Tgfbr2 mice were crossed with CAG-Cre mice with the coding sequences of Cre recombinase under control of a tamoxifen-responsive chicken actin promoter. The successful deletion of TβRII was confirmed by real time RT-PCR, Western blotting and immunohistochemistry. Retinal structure and function were studied by light and electron microscopy, immunohistochemistry, fluorescence angiography, real time RT-PCR, and electroretinography.
Treatment of newborn Tgfbr2-/-;CAG-Cre mice with tamoxifen resulted in a substantial and significant deletion of TβRII throughout the entire retina. Lack of TGF-β signaling led to the formation of abundant microaneurysms, leaky capillaries, and retinal hemorrhages. Retinal capillaries were not covered by differentiated pericytes, but by a coat of vascular smooth muscle-like cells and a thickened basal lamina. Reactive microglia was found in close association with retinal capillaries. In older animals, loss of endothelial cells and the formation of ghost vessels were observed, findings that correlated with the induction of angiogenic molecules such as VEGF-A, FGF-2, ANGPT2 and IGF and the accumulation of retinal HIF-1α indicating hypoxia. Consequently, retinal and vitreal neovascularization occurred, a scenario that led to retinal detachment, vitreal hemorrhages, neuronal apoptosis and impairment of sensory function.
TGF-β signaling is critically required for the differentiation of retinal pericytes during vascular development of the retina. Lack of differentiated pericytes initiates a scenario of structural and functional changes in the retina that mimics those of diabetic retinopathy and strongly indicates a common mechanism. We conclude that Tgfbr2-/-;CAG-Cre mice constitute an animal model to study the molecular pathogenesis of retinal diseases associated with neo-angiogenesis such as diabetic retinopathy.<br />
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