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All-trans-Retinaldehyde Contributes to Retinal Vascular Permeability in Ischemia Reperfusion

PURPOSE: Extracellular accumulation of all-trans-retinaldehyde (atRAL), a highly reactive visual cycle intermediate, is toxic to cells of the outer retina and contributes to retinal and macular degenerations. However, the contribution of atRAL to retinal capillary function has not been studied. We h...

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Autores principales: Dreffs, Alyssa, Lin, Cheng-Mao, Liu, Xuwen, Shanmugam, Sumathi, Abcouwer, Steven F., Kern, Timothy S., Antonetti, David A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Association for Research in Vision and Ophthalmology 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415894/
https://www.ncbi.nlm.nih.gov/pubmed/32492112
http://dx.doi.org/10.1167/iovs.61.6.8
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author Dreffs, Alyssa
Lin, Cheng-Mao
Liu, Xuwen
Shanmugam, Sumathi
Abcouwer, Steven F.
Kern, Timothy S.
Antonetti, David A.
author_facet Dreffs, Alyssa
Lin, Cheng-Mao
Liu, Xuwen
Shanmugam, Sumathi
Abcouwer, Steven F.
Kern, Timothy S.
Antonetti, David A.
author_sort Dreffs, Alyssa
collection PubMed
description PURPOSE: Extracellular accumulation of all-trans-retinaldehyde (atRAL), a highly reactive visual cycle intermediate, is toxic to cells of the outer retina and contributes to retinal and macular degenerations. However, the contribution of atRAL to retinal capillary function has not been studied. We hypothesized that atRAL released from the outer retina can contribute to retinal vascular permeability. We, therefore, tested the contribution of atRAL to retinal ischemia-reperfusion (IR)-induced vascular permeability. METHODS: IR was induced in mice by transient increase in intraocular pressure followed by natural reperfusion. The visual cycle was ablated in the Lrat(−)(/)(−) mice, reduced by dark adaptation or the use of the RPE65 inhibitor and atRAL scavenger emixustat. Accumulation of FITC-BSA was used to assess vascular permeability and DNA fragmentation quantified cell death after IR. Primary bovine retinal endothelial cell (BREC) culture was used to measure the direct effects of atRAL on endothelial permeability and cell death. RESULTS: Inhibition of the visual cycle by Lrat(−)(/)(−), dark adaptation, or with emixustat, all reduced approximately half of IR induced vascular permeability at 48 hours. An increase in BREC permeability with atRAL coincided with lactate dehydrogenase (LDH) release, a measure of cell death. Both permeability and toxicity were blocked by emixustat. CONCLUSIONS: Outer retinal pathology may contribute to vascular permeability by release of atRAL, which can act directly on vascular endothelial cells to alter barrier properties and induce cell death. These studies may have implications for a variety of blinding eye diseases that include outer retinal damage and retinal vascular permeability.
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spelling pubmed-74158942020-08-24 All-trans-Retinaldehyde Contributes to Retinal Vascular Permeability in Ischemia Reperfusion Dreffs, Alyssa Lin, Cheng-Mao Liu, Xuwen Shanmugam, Sumathi Abcouwer, Steven F. Kern, Timothy S. Antonetti, David A. Invest Ophthalmol Vis Sci Retina PURPOSE: Extracellular accumulation of all-trans-retinaldehyde (atRAL), a highly reactive visual cycle intermediate, is toxic to cells of the outer retina and contributes to retinal and macular degenerations. However, the contribution of atRAL to retinal capillary function has not been studied. We hypothesized that atRAL released from the outer retina can contribute to retinal vascular permeability. We, therefore, tested the contribution of atRAL to retinal ischemia-reperfusion (IR)-induced vascular permeability. METHODS: IR was induced in mice by transient increase in intraocular pressure followed by natural reperfusion. The visual cycle was ablated in the Lrat(−)(/)(−) mice, reduced by dark adaptation or the use of the RPE65 inhibitor and atRAL scavenger emixustat. Accumulation of FITC-BSA was used to assess vascular permeability and DNA fragmentation quantified cell death after IR. Primary bovine retinal endothelial cell (BREC) culture was used to measure the direct effects of atRAL on endothelial permeability and cell death. RESULTS: Inhibition of the visual cycle by Lrat(−)(/)(−), dark adaptation, or with emixustat, all reduced approximately half of IR induced vascular permeability at 48 hours. An increase in BREC permeability with atRAL coincided with lactate dehydrogenase (LDH) release, a measure of cell death. Both permeability and toxicity were blocked by emixustat. CONCLUSIONS: Outer retinal pathology may contribute to vascular permeability by release of atRAL, which can act directly on vascular endothelial cells to alter barrier properties and induce cell death. These studies may have implications for a variety of blinding eye diseases that include outer retinal damage and retinal vascular permeability. The Association for Research in Vision and Ophthalmology 2020-06-03 /pmc/articles/PMC7415894/ /pubmed/32492112 http://dx.doi.org/10.1167/iovs.61.6.8 Text en Copyright 2020 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
spellingShingle Retina
Dreffs, Alyssa
Lin, Cheng-Mao
Liu, Xuwen
Shanmugam, Sumathi
Abcouwer, Steven F.
Kern, Timothy S.
Antonetti, David A.
All-trans-Retinaldehyde Contributes to Retinal Vascular Permeability in Ischemia Reperfusion
title All-trans-Retinaldehyde Contributes to Retinal Vascular Permeability in Ischemia Reperfusion
title_full All-trans-Retinaldehyde Contributes to Retinal Vascular Permeability in Ischemia Reperfusion
title_fullStr All-trans-Retinaldehyde Contributes to Retinal Vascular Permeability in Ischemia Reperfusion
title_full_unstemmed All-trans-Retinaldehyde Contributes to Retinal Vascular Permeability in Ischemia Reperfusion
title_short All-trans-Retinaldehyde Contributes to Retinal Vascular Permeability in Ischemia Reperfusion
title_sort all-trans-retinaldehyde contributes to retinal vascular permeability in ischemia reperfusion
topic Retina
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415894/
https://www.ncbi.nlm.nih.gov/pubmed/32492112
http://dx.doi.org/10.1167/iovs.61.6.8
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