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Azza B El-Remessy, Sally L Elshaer; Deletion of P75NTR Stimulates Reparative Angiogenesis and Prevents Retinal Neovascularization in Ischemic Retinopathy: Possible contribution of TrkA receptor. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2447. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Ischemic retinopathy is characterized by an initial microvascular degeneration followed by a maladaptive pathological retinal neovascularization (RNV) resulting in impaired neuro-vascular function and visual impairment. There is urgent need to identify druggable targets to overcome ischemic retinopathy. Given the role of neuron-secreted growth factors in regulating angiogenesis, we examined the vascular protective effects of genetic deletion of the neurotrophin p75NTR receptor in an oxygen-induced retinopathy mouse model.
Vascular density, number of tip cells, and perfusions of capillaries were assessed. Western Blot and PCR were used to assess levels of growth factors including vascular endothelial growth factor (VEGF), nerve growth factor (NGF), brain-derived nerve factor (BDNF) and its precursor proNGF, proBDNF as well as expression and activation of the receptors, sortilin, TrkA and VEGFR2.
The results showed that deletion of p75NTR prevented hyperoxia-associated central vascular cell death and hypoxia-associated RNV and enhanced reparative angiogenesis compared to WT. These effects were associated with decreased expression of apoptotic markers; c-PARP, total PARP and preserved survival signal Akt and restored the balance of increased NGF and decreased proNGF at the hyperoxic stage. During hypoxia, deletion of p75NTR restored NGF/proNGF and BDNF/proBDNF levels, and maintained VEGF and VEGFR2 activation compared to WT. Deletion of p75NTR resulted in significant increases in expression and activation of TkA, while WT showed decreases in both. Pharmacological inhibition of TrkA using compound K-252a (0.5μg/1μl) resulted in 2-fold increase in RNV and 1.34-fold increase in capillary dropout in P75NTR KO mice, but not in WT compared to vehicle-injected controls.
Deletion of p75NTR protected against retinal ischemia, through restoring neurotrophins levels and activating TrkA receptor. Thus, targeting p75NTR offers potential therapeutic strategy for treatment of ischemic retinopathy.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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