title: Silencing p75(NTR) prevents proNGF-induced endothelial cell death and development of acellular capillaries in rat retina.
abstract: Accumulation of the nerve growth factor precursor (proNGF) and its receptor p75(NTR) have been associated with several neurodegenerative diseases in both brain and retina. However, whether proNGF contributes to microvascular degeneration remain unexplored. This study seeks to investigate the mechanism by which proNGF/p75(NTR) induce endothelial cell (EC) death and development of acellular capillaries, a surrogate marker of retinal ischemia. Stable overexpression of the cleavage-resistant proNGF and molecular silencing of p75(NTR) were utilized in human retinal EC and rat retinas in vivo. Stable overexpression of proNGF decreased NGF levels and induced retinal vascular cell death evident by 1.9-fold increase in acellular capillaries and activation of JNK and cleaved-PARP that were mitigated by p75(NTR)shRNA. In vitro, overexpression of proNGF did not alter TNF-α level, reduced NGF, however induced EC apoptosis evident by activation of JNK and p38 MAPK, cleaved-PARP. Silencing p75(NTR) using siRNA restored expression of NGF and TrkA activation and prevented EC apoptosis. Treatment of EC with human-mutant proNGF induced apoptosis that coincided with marked protein interaction and nuclear translocation of p75(NTR) and the neurotrophin receptor interacting factor. These effects were abolished by a selective p75(NTR) antagonist. Therefore, targeting p75(NTR) represents a potential therapeutic strategy for diseases associated with aberrant expression of proNGF.
authors.affiliation: Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia , Georgia, USA ; Culver Vision Discovery Institute, Georgia Regents University , Georgia, USA ; Charlie Norwood Veterans Affairs Medical Center , Augusta, Georgia, USA.
authors.forename: Ahmed Y
authors.initials: AY
authors.lastname: Shanab
authors.affiliation: Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia , Georgia, USA ; Culver Vision Discovery Institute, Georgia Regents University , Georgia, USA ; Charlie Norwood Veterans Affairs Medical Center , Augusta, Georgia, USA.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Mysona
authors.affiliation: Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia , Georgia, USA ; Culver Vision Discovery Institute, Georgia Regents University , Georgia, USA ; Charlie Norwood Veterans Affairs Medical Center , Augusta, Georgia, USA.
authors.forename: Suraporn
authors.initials: S
authors.lastname: Matragoon
authors.affiliation: Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia , Georgia, USA ; Culver Vision Discovery Institute, Georgia Regents University , Georgia, USA ; Charlie Norwood Veterans Affairs Medical Center , Augusta, Georgia, USA.
authors.forename: Azza B
authors.initials: AB
authors.lastname: El-Remessy