Inactivation of endothelial ADAM17 reduces retinal ischemia-reperfusion induced neuronal and vascular damage
Gutsaeva,Diana R.1; Shalaby,Lamiaa1; Powell,Folami L.2; Thounaojam,Menaka C.1; Abouhish,Hossameldin1,3; Wetzstein,Sara A.4; Jadeja,Ravirajsinh N.2; Kwok,Hang Fai5; Martin,Pamela M.2; Bartoli,Manuela1
Source PublicationInternational Journal of Molecular Sciences
AbstractRetinal 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.
KeywordADAM17 Neuronal and vascular degeneration Retinal ischemia-reperfusion Vascular permeability
URLView the original
Scopus ID2-s2.0-85089132081
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Document TypeJournal article
CollectionUniversity of Macau
Corresponding AuthorGutsaeva,Diana R.
Affiliation1.Department of Ophthalmology,Medical College of Georgia,Augusta University,Augusta,30912,United States
2.Department of Biochemistry and Molecular Biology,Medical College of Georgia,Augusta University,Augusta,30912,United States
3.Department of Clinical Pharmacology,Faculty of Medicine,Mansoura University,Mansoura,35516,Egypt
4.School of Medicine,Mercer University,Macon,31207,United States
5.Institute of Translational Medicine,Faculty of Health Sciences,University of Macau,Avenida de Universidade,Macao
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Gutsaeva,Diana R.,Shalaby,Lamiaa,Powell,Folami L.,et al. Inactivation of endothelial ADAM17 reduces retinal ischemia-reperfusion induced neuronal and vascular damage[J]. International Journal of Molecular Sciences,2020,21(15):1-18.
APA Gutsaeva,Diana R.,Shalaby,Lamiaa,Powell,Folami L.,Thounaojam,Menaka C.,Abouhish,Hossameldin,Wetzstein,Sara A.,Jadeja,Ravirajsinh N.,Kwok,Hang Fai,Martin,Pamela M.,&Bartoli,Manuela.(2020).Inactivation of endothelial ADAM17 reduces retinal ischemia-reperfusion induced neuronal and vascular damage.International Journal of Molecular Sciences,21(15),1-18.
MLA Gutsaeva,Diana R.,et al."Inactivation of endothelial ADAM17 reduces retinal ischemia-reperfusion induced neuronal and vascular damage".International Journal of Molecular Sciences 21.15(2020):1-18.
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