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Barbara Maria Braunger, Anja Schlecht, Sarah Leimbeck, Herbert Jaegle, Annette Feuchtinger, Ernst R Tamm; Ablation of endothelial TGF-β signaling causes choroidal neovascularization. Invest. Ophthalmol. Vis. Sci. 2017;58(8):810.
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The molecular pathogenesis of choroidal neovascularization (CNV), an angiogenic process that critically contributes to vision loss in age-related macular degeneration (AMD) is unclear. To identify the role of TGF-β signaling for CNV formation, we generated mice with a conditional deletion of the TGF-β type II (TβRII) receptor which is essential for TGF-β signaling.
We generated a series of mutant mouse models with induced conditional deletion of TGF-β signaling in the entire eye, the retinal pigment epithelium (RPE) or the vascular endothelium. To activate Cre recombinase, mice were treated with tamoxifen or doxycycline eye drops either as newborns or at the age of 3 weeks. The successful deletion of TβRII was confirmed by real time RT-PCR, Western blotting and immunohistochemistry. Retinal/choroidal structure and function were studied by light and transmission electron microscopy (TEM), immunohistochemistry, FITC-dextran perfusions, fluorescence angiography, CLARITY imaging, real time RT-PCR, and electroretinography.
Deletion of TGF-β signaling in the entire eye of newborn mice resulted in a significant upregulation of retinal Vegf-a, Fgf-2, Angpt2 and Igf expression levels, and markers for reactive microglia such as Cd68, iNos and Tnf-α. At the age of 6 weeks, CNV was detected by CLARITY imaging of the eyes of isolectin B4 injected animals and on meridional sections of dextran perfused eyes. Deletion of TGF-β signaling in the entire eye of three week old mice did not cause obvious changes of the retinal vasculature. However, CNV were still observed. TEM analyses showed the thickening of the Bruch’s membrane (BM) and fine fibrillar extracellular material between the basal lamina of the choriocapillaris and the elastic layer of BM. At the age of 6 months, ERG analyses showed functional deficits, and marked degenerative changes of the retinae were observed. While the specific deletion of TGF-β signaling in the RPE caused no obvious changes, specific deletion in vascular endothelial cells caused CNV and a phenotype quite similar to that observed after the deletion in the entire eye.
Impairment of TGF-β signaling in the vascular endothelium of the eye is sufficient to trigger CNV formation. Our findings highlight the importance of TGF-β signaling as key player in the development of CNV and indicate a fundamental role of TGF-β signaling in the pathogenesis of AMD.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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