Abstract
Retinal ischemia-reperfusion (IR) induces neurodegenaration as well as blood-retinal barrier (BRB) breakdown causing vascular permeability. Whereas the neuronal death has been extensively studied, the molecular mechanisms related to BRB breakdown in IR injury remain poorly understood. In this study, we investigated the early changes in tight junctional (TJ) proteins in response to IR injury. Ischemia-reperfusion injury was induced in male rat retinas by increasing the intraocular pressure for 45 minutes followed by natural reperfusion. The results demonstrate that IR injury induced occludin Ser490 phosphorylation and ubiquitination within 15 minutes of reperfusion with subsequent vascular permeability. Immunohistochemical analysis revealed a rapid increase in occludin Ser490 phosphorylation and loss of Zonula occludens-1 (ZO-1) protein, particularly in arterioles. Ischemia-reperfusion injury also rapidly induced the activation and phosphorylation of vascular endothelial growth factor receptor-2 (VEGFR-2) at tyrosine 1175. Blocking vascular endothelial growth factor (VEGF) function by intravitreal injection of bevacizumab prevented VEGFR-2 activation, occludin phosphorylation, and vascular permeability. These studies suggest a novel mechanism of occludin Ser490 phosphorylation and ubiquitination downstream of VEGFR2 activation associated with early IR-induced vascular permeability.
Highlights
Retinal ischemia–reperfusion models several components of various eye disease pathologies such as retinal vein occlusion, diabetic retinopathy, and glaucoma.[1,2,3,4,5,6] The IR model has been widely used for studying retinal neuronal cell damage after ischemic insult[6] and consists of transient ischemia followed by natural reperfusion leading to an inflammatory and neurodegenerative response in the intact retina.[7]
Ischemia–Reperfusion Induced Blood–Retinal Barrier Breakdown The effect of IR injury on blood–retinal barrier (BRB) breakdown was examined by inducing a mild ischemic insult in the rat retina as previously described.[3]
The results suggest that the IR injury alters the distribution of specific tight junction proteins at the BRB, and the resultant altered organization of tight junctional (TJ) proteins leads to vascular permeability
Summary
Retinal ischemia–reperfusion models several components of various eye disease pathologies such as retinal vein occlusion, diabetic retinopathy, and glaucoma.[1,2,3,4,5,6] The IR model has been widely used for studying retinal neuronal cell damage after ischemic insult[6] and consists of transient ischemia followed by natural reperfusion leading to an inflammatory and neurodegenerative response in the intact retina.[7]. A hypoxia-responsive angiogenic and vasopermeability factor, contributes to vascular leakage in multiple retinal pathologies.[10]
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