期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 34, 期 3, 页码 522-531出版社
SAGE PUBLICATIONS INC
DOI: 10.1038/jcbfm.2013.230
关键词
blood-retinal barrier; ischemia-reperfusion injury; occludin phosphorylation; tight junction; vascular endothelial growth factor; vascular permeability
资金
- JDRF
- NIH [R01 EY012021]
- Core Center for Vision Research at the Kellogg Eye Center [P30 EY007003]
- Research to Prevent Blindness Jules and Doris Stein Professorship
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. lschemia-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.
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