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Nat Commun ; 11(1): 3173, 2020 06 23.
Article in English | MEDLINE | ID: mdl-32576823

ABSTRACT

Central nervous system ischemic injury features neuronal dysfunction, inflammation and breakdown of vascular integrity. Here we show that activation of endothelial caspase-9 after hypoxia-ischemia is a critical event in subsequent dysfunction of the blood-retina barrier, using a panel of interrelated ophthalmic in vivo imaging measures in a mouse model of retinal vein occlusion (RVO). Rapid nonapoptotic activation of caspase-9 and its downstream effector caspase-7 in endothelial cells promotes capillary ischemia and retinal neurodegeneration. Topical eye-drop delivery of a highly selective caspase-9 inhibitor provides morphological and functional retinal protection. Inducible endothelial-specific caspase-9 deletion phenocopies this protection, with attenuated retinal edema, reduced inflammation and preserved neuroretinal morphology and function following RVO. These results reveal a non-apoptotic function of endothelial caspase-9 which regulates blood-retina barrier integrity and neuronal survival, and identify caspase-9 as a therapeutic target in neurovascular disease.


Subject(s)
Caspase 9/metabolism , Hypoxia/metabolism , Ischemia/metabolism , Retinal Vein Occlusion/metabolism , Vascular System Injuries/metabolism , Animals , Blood-Retinal Barrier/metabolism , Caspase 7/metabolism , Caspase 9/drug effects , Caspase 9/genetics , Cell Death , Disease Models, Animal , Endothelial Cells/metabolism , Female , Genetic Predisposition to Disease/genetics , Inflammation/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Rabbits , Retina/metabolism , Retina/pathology , Retinal Vein Occlusion/drug therapy , Retinal Vein Occlusion/pathology , Vascular System Injuries/pathology
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