Abstract
PurposeTo identify the protein profiles in vitreous associated with retinal fibrosis, angiogenesis, and neurite formation in epiretinal fibrovascular membranes (FVMs) in patients with proliferative diabetic retinopathy (PDR).MethodsVitreous samples of 5 non-diabetic control patients with vitreous debris and 7 patients with PDR membranes were screened for 507 preselected proteins using the semi-quantitative RayBio® L-series 507 antibody array. From this array, 60 proteins were selected for a custom quantitative antibody array (Raybiotech, Human Quantibody® array), analyzing 7 control patients, 8 PDR patients with FVMs, and 5 PDR patients without FVMs. Additionally, mRNA levels of proteins of interest were measured in 10 PDR membranes and 11 idiopathic membranes and in retinal tissues and cells to identify possible sources of protein production.ResultsOf the 507 proteins screened, 21 were found to be significantly elevated in PDR patients, including neurogenic and angiogenic factors such as neuregulin 1 (NRG1), nerve growth factor receptor (NGFR), placental growth factor (PlGF) and platelet derived growth factor (PDGF). Angiopoietin-2 (Ang2) concentrations were strongly correlated to the degree of fibrosis and the presence of FVMs in patients with PDR. Protein correlation analysis showed PDGF to be extensively co-regulated with other proteins, including thrombospondin-1 and Ang2. mRNA levels of glial-derived and brain/derived neurotrophic factor (GDNF and BDNF) were elevated in PDR membranes. These results were validated in a second study of 52 vitreous samples of 32 PDR patients and 20 control patients.ConclusionsThis exploratory study reveals protein networks that potentially contribute to neurite outgrowth, angiogenesis and fibrosis in the formation of fibrovascular membranes in PDR. We identified a possible role of Ang2 in fibrosis and the formation of FVMs, and of the neurotrophic factors NRG1, PDGF and GDNF in neurite growth that occurs in all FVMs in PDR.
Highlights
Proliferative diabetic retinopathy (PDR) is a serious ocular complication of diabetes and is characterized by retinal neovascularization and microvascular leakage in response to chronic ischemia
Angiopoietin-2 (Ang2) concentrations were strongly correlated to the degree of fibrosis and the presence of fibrovascular membranes (FVMs) in patients with proliferative diabetic retinopathy (PDR)
platelet derived growth factor (PDGF) to be extensively co-regulated with other proteins, including thrombospondin-1 and Ang2. mRNA levels of glial-derived and brain/derived neurotrophic factor (GDNF and BDNF) were elevated in PDR membranes. These results were validated in a second study of 52 vitreous samples of 32 PDR patients and 20 control patients. This exploratory study reveals protein networks that potentially contribute to neurite outgrowth, angiogenesis and fibrosis in the formation of fibrovascular membranes in PDR
Summary
Proliferative diabetic retinopathy (PDR) is a serious ocular complication of diabetes and is characterized by retinal neovascularization and microvascular leakage in response to chronic ischemia. There have been concerns that anti-VEGF treatment may temporarily increase fibrovascular membrane (FVM) formation and retinal traction [3,4,5,6,7] Both retinal detachment and hemorrhages in PDR are the leading causes of permanent vision loss or blindness in adults of working age [8,9]. It has been shown that PDR-associated FVMs contain neurite extensions growing alongside Muller cells, a specialized type of retinal glia cell [12]. New vessel growth is orchestrated by chemoattractant and trophic factors derived from neurons [15] and Muller cells [16], and Muller cells serve as a scaffold for new vasculature [17] Under these conditions, retinal glial cells, macrophages, monocytes, hyalocytes (resident cells in the vitreous), fibroblasts, pericytes and vascular endothelial cells will migrate and proliferate into the vitreous body, hereby forming FVMs [18,19]. The cause and pathological implications of early neurite recruitment in FVMs and their contribution to retinal angiogenesis and fibrosis are still unknown
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