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Mohammed A. Abdelsaid, Azza B. El-Remessy; Thioredoxin-interacting Protein Is Required For VEGF’s Survival And Angiogenic Signal. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4849.
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Vascular endothelial growth factor (VEGF) is a key player in retinal neovascularization. We have previously shown that while low levels of peroxynitrite are required to transduce VEGF’s angiogenic signal, high levels of peroxynitrite impair VEGF’s survival signal suggesting the need for a balanced redox state. Thioredoxin inhibiting protein (TXNIP), the endogenous inhibitor of the major antioxidant thioredoxin system, can regulate cellular redox state. Therefore, we will examine the critical role of TXNIP in modulating retinal redox state and VEGF’s signal in vivo and in vitro.
Mice with non-sense mutation of TXNIP (TKO) and wild type were subjected to ischemic retinopathy model. Retinal central capillary dropout was measured at p12 and physiological revascularization and pathological neovascularization were assessed at p17. Retinal redox state was assessed by measuring the reduced glutathione (GSH), nitrotyrosine formation and thioredoxin reductase activity. Human retinal endothelial (HRE) cells were used to examine VEGF’s effects on redox state and cell migration.
Retinas of TKO mice experienced reductive stress as indicated by significant increases in the thioredoxin reductase activity, GSH levels and reduction in peroxynitrite formation. In comparison to wild type mice, TKO mice showed exacerbated capillary dropout area in response to hyperoxia and impaired physiological revascularization and less retinal neovascularization in response to hypoxia. In HRE cells, VEGF shifted the redox state to oxidative sate transiently, which was reversed by NAC, a thiol donor; or FeTPPS, peroxynitrite decomposition catalyst. Altering the redox state with NAC, FeTPPS or silencing TXNIP expression significantly reduced VEGF-mediated endothelial migration.
Our results emphasize the great importance of TXNIP expression for achieving the balance in redox state required for VEGF’s survival and angiogenic signal. A better understanding for VEGF redox signaling will identify new therapeutic targets to control the angiogenic process.
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