Abstract
Pathological angiogenesis is a major cause of vision loss in ischemic and inflammatory retinal diseases. Recent evidence implicates macrophage metalloelastase (MMP-12), a macrophage-derived elastinolytic protease in inflammation, tissue remodeling and angiogenesis. However, little is known about the role of MMP-12 in retinal pathophysiology. The present study aims to explore the enzyme’s contributions to retinal angiogenesis in oxygen-induced retinopathy (OIR) using MMP-12 knockout (KO) mice. We find that MMP-12 expression was upregulated in OIR, accompanied by elevated macrophage infiltration and increased inflammatory markers. Compared to wildtype mice, MMP-12 KO mice had decreased levels of adhesion molecule and inflammatory cytokines and reduced vascular leakage in OIR. Concomitantly, these mice had markedly reduced macrophage content in the retina with impaired macrophage migratory capacity. Significantly, loss of MMP-12 attenuated retinal capillary dropout in early OIR and mitigated pathological retinal neovascularization (NV). Similar results were observed in the study using MMP408, a pharmacological inhibitor of MMP-12. Intriguingly, in contrast to reducing pathological angiogenesis, lack of MMP-12 accelerated revascularization of avascular retina in OIR. Taken together, we conclude that MMP-12 is a key regulator of macrophage infiltration and inflammation, contributing to retinal vascular dysfunction and pathological angiogenesis.
Highlights
Overgrowth of new vessels is a major cause of blindness in several sight-threatening diseases, such as retinopathy of prematurity (ROP), diabetic retinopathy (DR) and the wet form of age-related macular degeneration (AMD)
To determine if deficiency of matrix metalloproteinases (MMPs)-12 affects retinal development, histological studies were performed on retinal sections of WT and MMP-12 KO mice aged from postnatal day 17 (P17) to 6 months
Emerging evidence suggests that macrophage infiltration and macrophage-mediated inflammation play pivotal roles in the pathogenesis of retinal vaso-obliteration and pathological retinal NV [2]
Summary
Overgrowth of new vessels (neovascularization, NV) is a major cause of blindness in several sight-threatening diseases, such as retinopathy of prematurity (ROP), diabetic retinopathy (DR) and the wet form of age-related macular degeneration (AMD). The pathogenesis of retinal NV associates closely with ischemia resulting from vascular cell death and capillary dropout in the inner retina. Independent studies demonstrate that the number of macrophages increases significantly in the vitreous as well as in the retina of animals with OIR [4,5]. Mutation of macrophage colony-stimulating factor (M-CSF), a cytokine required for the differentiation of monocyte lineage cells into mature macrophages, reduces retinal NV in OIR [5]. These findings suggest that macrophage activation and infiltration contributes to the pathogenesis of retinal NV. The mechanisms that regulate macrophage infiltration and enable the cells to promote angiogenesis are not fully understood
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