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Sally Lotfy Elshaer, Azza B El-Remessy; Modulation of P75NTR Restores Reparative Angiogenesis and Prevents Retinal Neovascularization in Ischemic Retinopathy.. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4916.
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© ARVO (1962-2015); The Authors (2016-present)
We have previously shown that the nerve growth factor (NGF) precursor, proNGF induced angiogenic response in bovine retinal endothelial cells (BRE) via activation of the survival receptor TrkA. Interestingly, inhibition of the neurotrophin receptor p75NTR did not mitigate proNGF-induced angiogenic response but enhanced TrkA activation. Here, we attempted to study the contribution of p75NTR receptor in retinal angiogenesis in vitro and in vivo.
Wild type (WT) or p75NTR KO mice were subjected to oxygen-induced retinopathy model and vascular density was assessed at p17. BRE cultures were treated with mutant-proNGF in the presence or absence of the specific inhibitor of p75NTR provided by Dr. Saragovi, McGill University. Expression of NGF, proNGF, sortilin and p75NTR as well as activation of TrkA, Akt, and ERK 1,2 were assessed by Western blot in cells and retinal lysate.
At p17, hypoxia induced peripheral vascular tufts (~60%) in WT but not in p75KO retinas. Deletion of p75NTR enhanced reparative angiogenesis as indicated by significant reduction (80%) of central capillary dropout area compared to WT. Retinal lysate from WT-hypoxia showed significant increases in proNGF and sortilin expression, decreases in Akt activation by p14 and increased NGF expression by p17 compared to WT-normoxia. Deletion of p75NTR maintained increased sortilin expression and restored expression of proNGF, NGF and activation of Akt back to normal levels. In BRE cultures, mutant-proNGF (50ng/ml) activates TrkA, Akt and ERK-1,2. Inhibition of p75NTR induced sortilin expression and enhanced activation of TrkA, Akt, ERK1-2 in mutant proNGF-treated or untreated cells.
Deletion of p75NTR prevented pathological retinal neovascularization and enhanced reparative central capillary growth by restoring balance of NGF and proNGF levels. In BRE cells, inhibition of p75NTR receptor enhanced proNGF-mediated sortilin expression and activation of TrkA, ERK-1,2- and Akt pathway. Thus, inhibition of p75NTR can provide potential therapeutic targets for ischemic retinopathy.
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