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Inactivation of Endothelial ADAM17 Reduces Retinal Ischemia-Reperfusion Induced Neuronal and Vascular Damage.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2020 Jul 29; Vol. 21 (15). Date of Electronic Publication: 2020 Jul 29. - Publication Year :
- 2020
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Abstract
- Retinal ischemia contributes to visual impairment in ischemic retinopathies. A disintegrin and metalloproteinase ADAM17 is implicated in multiple vascular pathologies through its ability to regulate inflammatory signaling via ectodomain shedding. We investigated the role of endothelial ADAM17 in neuronal and vascular degeneration associated with retinal ischemia reperfusion (IR) injury using mice with conditional inactivation of ADAM17 in vascular endothelium. ADAM17Cre-flox and control ADAM17flox mice were subjected to 40 min of pressure-induced retinal ischemia, with the contralateral eye serving as control. Albumin extravasation and retinal leukostasis were evaluated 48 h after reperfusion. Retinal morphometric analysis was conducted 7 days after reperfusion. Degenerate capillaries were assessed by elastase digest and visual function was evaluated by optokinetic test 14 and 7 days following ischemia, respectively. Lack of ADAM17 decreased vascular leakage and reduced retinal thinning and ganglion cell loss in ADAM17Cre-flox mice. Further, ADAM17Cre-flox mice exhibited a remarkable reduction in capillary degeneration following IR. Decrease in neurovascular degeneration in ADAM17Cre-flox mice correlated with decreased activation of caspase-3 and was associated with reduction in oxidative stress and retinal leukostasis. In addition, knockdown of ADAM17 resulted in decreased cleavage of p75NTR, the process known to be associated with retinal cell apoptosis. A decline in visual acuity evidenced by decrease in spatial frequency threshold observed in ADAM17flox mice was partially restored in ADAM17-endothelial deficient mice. The obtained results provide evidence that endothelial ADAM17 is an important contributor to IR-induced neurovascular damage in the retina and suggest that interventions directed at regulating ADAM17 activity can be beneficial for alleviating the consequences of retinal ischemia.
- Subjects :
- ADAM17 Protein deficiency
Albumins metabolism
Animals
Apoptosis genetics
Capillary Permeability
Caspase 3 genetics
Caspase 3 metabolism
Cell Adhesion
Disease Models, Animal
Endothelium, Vascular metabolism
Endothelium, Vascular pathology
Gene Expression Regulation
Leukocytes metabolism
Leukocytes pathology
Leukostasis metabolism
Leukostasis pathology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Oxidative Stress
Receptors, Nerve Growth Factor genetics
Receptors, Nerve Growth Factor metabolism
Reperfusion Injury metabolism
Reperfusion Injury pathology
Retinal Degeneration metabolism
Retinal Degeneration pathology
Retinal Ganglion Cells pathology
ADAM17 Protein genetics
Leukostasis genetics
Reperfusion Injury genetics
Retinal Degeneration genetics
Retinal Ganglion Cells metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 21
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 32751103
- Full Text :
- https://doi.org/10.3390/ijms21155379