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Diana Gutsaeva, Lamiaa Shalaby, Sara Wetzstein, Menaka Thounaojam, Ravirajsinh Jadeja, Folami Lamoke Powell, Pamela M Martin, Hang Fai Kwok, Manuela Bartoli; Inactivation of Endothelial ADAM17 Reduces Retinal Ischemia-Reperfusion Induced Neurovascular Abnormalities. Invest. Ophthalmol. Vis. Sci. 2020;61(7):1785.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal ischemia contributes to visual impairment in ischemic retinopathies such as diabetic retinopathy and other potentially blinding conditions. A member of the ADAM family of a disintegrin and metalloproteinases, ADAM17, contributes to multiple vascular pathologies through its ability to regulate inflammatory signals via ectodomain shedding. Here we investigated the specific contribution of endothelial ADAM17 to neurovascular damage associated with retinal ischemia using a mouse model of ischemia-reperfusion (IR) injury.
Mice lacking endothelial ADAM17 were generated by crossing mice carrying floxed alleles of ADAM17 (Adam17tm1.2Bbl/J) with a strain of VE-Cadherin Cre mice (B6.Cg-Tg(Cdh5-cre)7Mlia/J). ADAM17flox (control) and ADAM17Cre-flox mice were subjected to pressure-induced retinal ischemia, with the contralateral eye serving as control. Vascular leakage was assessed 48 hours after ischemia by measuring albumin extravasation in perfused retinas by Western blotting. Morphometric analysis of hematoxylin/eosin stained retinal cryosections was conducted 7 days after ischemia. Tight junction (TJ) proteins were assessed by Western blotting. Acellular capillaries formation was evaluated 14 days after ischemia using the elastase-digest method. Visual acuity was analyzed using a visuomotor behavior assessment system.
IR increased vascular permeability in ADAM17flox mice, as demonstrated by increased levels of extravascular albumin and this effect was significantly diminished in ADAM17Cre-flox mice. The decrease in vascular leakage in the injured eyes of ADAM17Cre-flox mice was associated with recovery of the levels of TJ proteins ZO-1 and JAM-A. Knockdown of ADAM17 reduced acellular capillaries formation in IR eyes compared to contralateral eyes. In control mice, IR injury decreased total retinal and inner nuclear layer thickness and diminished the number of nuclei in the ganglion cell layer. These effects were significantly reduced in mice lacking endothelial ADAM17. In addition, a reduction in spatial frequency threshold in IR-injured eyes of ADAM17flox mice was significantly recovered in ADAM17Cre-flox mice.
Our data provide evidence that endothelial ADAM17 is an important contributor to IR-induced neurovascular abnormalities and suggest that interventions directed at regulating ADAM17 activity can alleviate the consequences of retinal ischemia.
This is a 2020 ARVO Annual Meeting abstract.
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