title: Pronerve growth factor induces angiogenesis via activation of TrkA: possible role in proliferative diabetic retinopathy.
abstract: Proliferative diabetic retinopathy (PDR) is the leading cause of blindness in working age Americans. We demonstrated that diabetes disturbs the homeostasis of nerve growth factor (NGF) resulting in accumulation of its precursor proNGF. Increases in proNGF were positively correlated with progression of diabetic retinopathy, having the highest level in ocular fluids from PDR patients compared to nondiabetic patients. Here, we attempted to evaluate the contribution and the possible mechanism of proNGF to PDR. The angiogenic response of aqueous humor samples from PDR patients was examined in human retinal endothelial cells in the presence or absence of anti-proNGF antibody. Additional cultures were treated with mutant-proNGF in the presence of specific pharmacological inhibitors of TrkA and p75(NTR) receptors. PDR-aqueous humor samples exerted significant angiogenic response including cell proliferation, migration, and alignment into tube-like structures. These effects were significantly reduced by anti-proNGF antibody but not by IgG. Treatment of retinal endothelial cells with mutant-proNGF activated phosphorylation of TrkA and p38MAPK; however, it did not alter p75(NTR) expression. Inhibition of TrkA but not p75(NTR) significantly reduced mutant-proNGF-induced cell proliferation, cell migration, and tube formation. Taken together, these results provide evidence that proNGF can contribute to PDR at least in part via activation of TrkA.
authors.affiliation: Center for Pharmacy and Experimental Therapeutics, University of Georgia, 1120 15th Street HM-1200, Augusta, GA 30912, USA.
authors.forename: Sally L
authors.initials: SL
authors.lastname: Elshaer
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Abdelsaid
authors.forename: Ahmad
authors.initials: A
authors.lastname: Al-Azayzih
authors.forename: Parag
authors.initials: P
authors.lastname: Kumar
authors.forename: Suraporn
authors.initials: S
authors.lastname: Matragoon
authors.forename: Julian J
authors.initials: JJ
authors.lastname: Nussbaum
authors.forename: Azza B
authors.initials: AB
authors.lastname: El-Remessy
mesh_terms: D000293:Adolescent; D000328:Adult; D001082:Aqueous Humor / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D003930:Diabetic Retinopathy / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000378:metabolism*; D010766:Phosphorylation; D011498:Protein Precursors / Q000378:metabolism*; D020917:Receptor, trkA / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D011498:Protein Precursors; C061397:pro-nerve growth factor, human; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D048051:p38 Mitogen-Activated Protein Kinases