Hindawi Publishing Corporation Journal of Diabetes Research Volume 2013, Article ID 432659, 10 pages http://dx.doi.org/10.1155/2013/432659 Research Article Pronerve Growth Factor Induces Angiogenesis via Activation of TrkA: Possible Role in Proliferative Diabetic Retinopathy Sally L. Elshaer, 1,2,3 Mohammed A. Abdelsaid, 1,2,3,4 Ahmad Al-Azayzih, 1,3 Parag Kumar, 1,5 Suraporn Matragoon, 1,2,3 Julian J. Nussbaum, 2 and Azza B. El-Remessy 1,2,3 1 Center for Pharmacy and Experimental herapeutics, University of Georgia, 1120 15th Street HM-1200, Augusta, GA 30912, USA 2 Culver Vision Discovery Institute, Georgia Reagents University, Augusta, GA 30912, USA 3 Charlie Norwood VA Medical Center, Augusta, GA 30912, USA 4 Department of Physiology, Georgia Reagents University, Augusta, Georgia 30912, USA 5 Pharmacy Department, National Institutes of Health Clinical Center, Bethesda, MD 20892, USA Correspondence should be addressed to Azza B. El-Remessy; aelremessy@gru.edu Received 30 April 2013; Revised 4 July 2013; Accepted 12 July 2013 Academic Editor: Mohamed Al-Shabrawey Copyright © 2013 Sally L. Elshaer et al. his is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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 luids from PDR patients compared to nondiabetic patients. Here, we attempted to evaluate the contribution and the possible mechanism of proNGF to PDR. he 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 speciic pharmacological inhibitors of TrkA and p75 NTR receptors. PDR-aqueous humor samples exerted signiicant angiogenic response including cell proliferation, migration, and alignment into tube-like structures. hese efects were signiicantly 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 signiicantly 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. 1. Introduction Diabetic retinopathy (DR) is the leading cause of blindness among working aged adults in the US. It afects 80% of individuals with a 10-year history of diabetes, adding 63,000 new cases of DR each year [1]. DR is characterized by neuro- and vascular degeneration that eventually lead to ischemia and subsequent release of angiogenic growth factors including vascular endothelial growth factor (VEGF) into the vitreous cavity resulting in retinal neovascularization and proliferative diabetic retinopathy (PDR) [2, 3]. PDR is char- acterized by vitreous hemorrhage, neovascular glaucoma, and tractional retinal detachment, which can result in visual loss [4]. Current treatment options for PDR include laser photocoagulation and anti-VEGF ocular injection, which are invasive and limited by side efects. Repeated injections of anti-VEGF can deprive the retina from the survival actions of VEGF on neurons and vasculature (reviewed in [2, 5]). herefore, there is a great need to identify contributing factors in PDR other than VEGF; in the hope of devising treatments that will preserve both retina vasculature and neuronal function. Diabetes-induced oxidative stress disturbs retinal home- ostasis by activating glial cells, reducing neurotrophic sup- port, and increasing proinlammatory cytokines including VEGF, IL-1, and TNF- [6, 7]. In addition to these known growth factors, recent indings using ocular luids from diabetic patients and experimental models of diabetes suggest