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

Nat Commun. 2020 Jun 23;11(1):3173. doi: 10.1038/s41467-020-16902-5.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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


  • Casp9 protein, mouse
  • Caspase 7
  • Caspase 9