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 p75NTR 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 p75NTR expression. Inhibition of TrkA but not p75NTR 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.

Deletion of the Neurotrophin Receptor p75NTR Prevents Diabetes-Induced Retinal Acellular Capillaries in Streptozotocin-Induced Mouse Diabetic Model

“…This observation is critical in the light of recent findings that proNGF can switch between neurotropic and apoptotic activity in response to changes in TrkA receptor levels [31]. Our results lend further support to the interplay between p75 NTR expression and TrkA activation previously demonstrated in retinal endothelial cells [17,32] and in hypoxia-induced retinal neovascularization model [33]. However, this is the first report that shows that deletion of p75 NTR can restore NGF and TrkA activation in the diabetic animals.…”

Vasoregression: A Shared Vascular Pathology Underlying Macrovascular And Microvascular Pathologies?

“…Elevated levels of ProNGF in ocular fluids from proliferative DR patients, raises a possibility that proNGF can contribute to development of proliferative stages of the disease. ProNGF also induces a potent angiogenic response in retinal EC that gets blocked by TrkA inhibition, suggesting the contribution of proNGF to proliferative DR, via activation of TrkA (Elshaer et al, 2013).…”

Implication of the neurotrophin receptor p75NTRin vascular diseases: beyond the eye

“…Previous literature identified clear angiogenic effects of NGF via activation of TrkA in models of angiogenesis [81]. Our group was the first to show that proNGF can be a potential player in angiogenic behavior in PDR [82]. Interestingly, proNGF was shown to mediate angiogenic signal at least in part through activation of TrkA receptor.…”

“…Furthermore, inhibition of p75 NTR did not significantly alter angiogenic response of retinal ECs to exogenous proNGF. Yet, its inhibition was associated with enhanced TrkA activation [82]. These findings highlight the cross talk between the two main receptors for neurotrophins: Trk and p75 NTR .…”