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.
Highlights
Central nervous system ischemic injury features neuronal dysfunction, inflammation and breakdown of vascular integrity
disorganization of retinal inner layers (DRIL) is a robust clinical measure of capillary ischemia[32,33], that is predictive of visual acuity loss in RVO34–37 and other retinopathies[38,39]
Prior studies of central nervous system (CNS) ischemic injury have demonstrated that hypoxia/ischemia induces temporal and spatial changes in neuronal function and vascular integrity, but it has not been elucidated whether these events are mechanistically integrated or separate pathways
Summary
Central nervous system ischemic injury features neuronal dysfunction, inflammation and breakdown of vascular integrity. 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). 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 nonapoptotic 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. The central nervous system (CNS) is one of the most metabolically active tissues in the body, rendering it exquisitely sensitive to vascular dysfunction; decreases in blood flow lead to hypoxia and ischemia which induce both neuronal loss and an increase in vascular permeability. In contrast to the well-studied role of caspases in neuronal death, less is known about caspase signaling in ischemic vasculature and studies have offered conflicting conclusions regarding endothelial cell death in retinal hypoxia–ischemia injury[22,23]
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