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Diana Gutsaeva, Menaka Thounaojam, Amany M Tawfik, Ravirajsinh Jadeja, Pamela M Martin, Wan Jin Jahng, Manuela Bartoli; Loss of endothelial TACE-ADAM17 reduces retinal vascular hyperpermeability and improves retinal morphology in diabetic mice. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2733.
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© ARVO (1962-2015); The Authors (2016-present)
The cell surface metalloproteinase ADAM17 (a disintegrin and metalloproteinase 17, also referred to as TNFα-converting enzyme, TACE) is an important regulator of inflammatory responses due to its sheddase activity towards cytokines, cytokine receptors, growth factors, and adhesion molecules. We have previously demonstrated that overactivation of ADAM17 is involved in the regulation of paracellular permeability in retinal microvascular cells. The main goal of this study was to investigate further the contribution of vascular ADAM17 to the pathogenesis of diabetic retinopathy (DR).
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). Control ADAM17flox/flox and ADAM17flox/flox/Cadh-Cre mice were made diabetic by 5 consecutive intraperitoneal injections of 55 mg/kg streptozotocin (STZ). Vascular leakage in STZ-treated ADAM17flox/flox and ADAM17flox/flox/Cadh-Cre mice was assessed 8 weeks post-onset of diabetes by fluorescein angiography (FA) and albumin extravasation by Western blotting analysis. Retinal structure was evaluated by Optical coherence tomography (OCT). Retinal morphology was evaluated in hematoxylin/eosin stained retinal cryosections. Retinal cell death was evaluated by TUNEL assay.
Hyperglycemia promoted an increase in vascular permeability in ADAM17flox/flox mice as shown by increased levels of extravascular albumin and perivascular fluorescein in surrounding tissue. These effects were significantly diminished in ADAM17flox/flox/Cadh-Cre mice. Morphologic analysis of hematoxylin/eosin stained retinal sections of STZ-induced diabetic ADAM17flox/flox mice showed an accumulation of inflammatory cells, reduced retinal thickness, and decreased number of cells in ganglion cell layer, whereas, STZ-induced diabetic ADAM17flox/flox/Cadh-Cre mice demonstrated much improved pathology. An increased number of TUNEL-positive cells evident in retinas of diabetic ADAM17flox/flox mice was significantly reduced in ADAM17flox/flox/Cadh-Cre mice.
The sum of the obtained results directly implicates endothelial-derived ADAM17 in DR related complications and suggests ADAM17 as a therapeutic target for diabetic macular edema.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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