Endothelial activation of caspase-9 promotes neurovascular injury in retinal vein occlusion
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 23, 2020
- Source ID
- 10.1038/s41467-020-16902-5
Entities
People
- Alexandra J. White
- Anna M Potenski
- Carol M Troy
- Claire W Chen
- Crystal Colon Ortiz
- Elisa Canepa
- Fatima N. Morales
- Guy S. Salvesen
- Jacqueline M Lawson
- Kendra V Johnson
- Maria I Avrutsky
- Scott J Snipas
- Stephanie K. Yuen
- Ying Y Jean
Organizations
- National Eye Institute
- National Institute of Neurological Disorders and Stroke
- National Institute on Aging
- National Science Foundation
- United States Department of Defense
- United States Department of Health and Human Services