%0 Journal Article
%T Pronerve Growth Factor Induces Angiogenesis via Activation of TrkA: Possible Role in Proliferative Diabetic Retinopathy
%A Sally L. Elshaer
%A Mohammed A. Abdelsaid
%A Ahmad Al-Azayzih
%A Parag Kumar
%A Suraporn Matragoon
%A Julian J. Nussbaum
%A Azza B. El-Remessy
%J Journal of Diabetes Research
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/432659
%X 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 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 expression. Inhibition of TrkA but not 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. 1. Introduction Diabetic retinopathy (DR) is the leading cause of blindness among working aged adults in the US. It affects 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 characterized 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 effects. Repeated injections of anti-VEGF can deprive the retina from the survival actions of VEGF on neurons and vasculature (reviewed in [2, 5]). Therefore, 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
%U http://www.hindawi.com/journals/jdr/2013/432659/