Relationship between vitreous levels of matrix metalloproteinases and vascular endothelial growth factor in proliferative diabetic retinopathy.

Ahmed M Abu El-Asrar,Mohd Imtiaz Nawaz,Kathleen Van Den Eynde,Gert De Hertogh,Ghulam Mohammad,Mohammad Mairaj Siddiquei,Ghislain Opdenakker,Ahmed Mousa

doi:10.1371/journal.pone.0085857

Ahmed M Abu El-Asrar, Mohd Imtiaz Nawaz + Show 6 more

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https://doi.org/10.1371/journal.pone.0085857

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To investigate which matrix metalloproteinases (MMPs) are more likely to be involved in the angiogenic process in proliferative diabetic retinopathy (PDR), we measured the levels of MMPs in the vitreous fluid from patients with PDR and controls and correlated these levels with the levels of vascular endothelial growth factor (VEGF). Vitreous samples from 32 PDR and 24 nondiabetic patients were studied by mosaic multiplex MMPs enzyme-linked immunosorbent assay (ELISA), single ELISA, Western blot and zymography analysis. Epiretinal membranes from 11 patients with PDR were studied by immunohistochemistry. MMP-8 and MMP-13 were not detected. ELISA, Western blot and gelatin ymography assays revealed significant increases in the expression levels of MMP-1, MMP-7, MMP-9 and VEGF in vitreous samples from PDR patients compared to nondiabetic controls, whereas MMP-2 and MMP-3 were not upregulated in vitreous samples from PDR patients. Significant correlations existed between ELISA and zymography assays for the quantitation of MMP-2 (r=0.407; p=0.039) and MMP-9 (r=0.711; p<0.001). Significant correlations were observed between levels of VEGF and levels of MMP-1 (r=0.845; P<0.001) and MMP-9 (r=0.775; p<0.001), and between levels of MMP-1 and MMP-9 (r=0.857; p<0.001). In epiretinal membranes, cytoplasmic immunoreactivity for MMP-9 was present in vascular endothelial cells and stromal monocytes/macrophages and neutrophils. Our findings suggest that among the MMPs measured, MMP-1 and MMP-9 may contribute to the angiogenic switch in PDR.

Highlights

Proliferative diabetic retinopathy (PDR), a long-term complication of diabetes, is characterized by vasculopathy associated with abnormal angiogenesis and expansion of extracellular matrix (ECM) resulting in the outgrowth of fibrovascular membranes at the vitreoretinal interface
matrix metalloproteinases (MMPs)-8 and MMP-13 were not detected in vitreous samples from patients with PDR (n=16) and nondiabetic control patients (n=24)
Among the MMPs examined, MMP-1, MMP-2, MMP-3, and MMP-7 were detected in all vitreous samples from patients with PDR and control patients without diabetes

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Introduction

Proliferative diabetic retinopathy (PDR), a long-term complication of diabetes, is characterized by vasculopathy associated with abnormal angiogenesis and expansion of extracellular matrix (ECM) resulting in the outgrowth of fibrovascular membranes at the vitreoretinal interface. Angiogenesis, the sprouting of new blood vessels from preexisting blood vessels, is a multistep process requiring the degradation of the basement membranes and ECM, endothelial cell migration, endothelial cell proliferation, and capillary tube formation [1]. The angiogenic switch involves in part the proteolytic degradation of basement membranes and ECM components by matrix metalloproteinases (MMPs). In addition to removing the physical barriers to new vessel growth, MMPs proteolytically release VEGF from the ECM-associated reservoirs [3,4], resulting in increased VEGF bioavailability and triggering the VEGF-driven angiogenic switch [3,4]. Most of the MMPs are inhibited by specific endogenous tissue inhibitors which are known as tissue inhibitors of matrix metalloproteinases (TIMPs) [5]

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