Endothelial activation of caspase-9 promotes neurovascular injury in retinal vein occlusion

Maria I. Avrutsky, Crystal Colón Ortiz, Kendra V. Johnson, Anna M. Potenski, Claire W. Chen, Jacqueline M. Lawson, Alexandra J. White, Stephanie K. Yuen, Fatima N. Morales, Elisa Canepa, Scott Snipas, Guy S. Salvesen, Ying Y. Jean and Carol M. Troy ()
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Maria I. Avrutsky: Columbia University
Crystal Colón Ortiz: Columbia University
Kendra V. Johnson: Columbia University
Anna M. Potenski: Columbia University
Claire W. Chen: Columbia University
Jacqueline M. Lawson: Columbia University
Alexandra J. White: Columbia University
Stephanie K. Yuen: Columbia University
Fatima N. Morales: Columbia University
Elisa Canepa: Columbia University
Scott Snipas: Sanford Burnham Prebys Medical Discovery Institute La Jolla
Guy S. Salvesen: Sanford Burnham Prebys Medical Discovery Institute La Jolla
Ying Y. Jean: Columbia University
Carol M. Troy: Columbia University

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16902-5

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