Abstract
Age-related macular degeneration (AMD), especially neovascular AMD with choroidal neovascularization (CNV), is the leading cause of blindness in the elderly. Although matrix metalloproteinases (MMPs) are involved in pathological ocular angiogenesis, including CNV, the cellular origin of MMPs in AMD remains unknown. The present study investigated the role of microglial MMPs in CNV. MMP activities were analyzed by gelatin zymography in aqueous humor samples from patients with CNV and laser-induced CNV mice. Active MMP-9 was increased in the aqueous humor samples from neovascular AMD patients compared with control subjects. In the retinal pigment epithelium (RPE)/choroid from CNV mice, active MMP-9 increased, beginning 1 h post-CNV induction, and remained upregulated until Day 7. In RPE/choroid from CNV mice, active MMP-9 was suppressed by minocycline, a known microglial inhibitor, at 6 h and 1-day post-CNV induction. Flow cytometry revealed that the proportion of activated microglia increased very early, beginning at 1 h post-CNV induction, and was maintained until Day 7. Similarly, immunohistochemistry revealed increased microglial activation and MMP-9 expression on CNV lesions at 6 h and 1-day post-CNV induction. SB-3CT, an MMP inhibitor, decreased vascular leakage and lesion size in laser-induced CNV mice. These findings indicated nearly immediate recruitment of activated microglia and very early MMP-9 activation in the RPE/choroid. The present study newly identified a potential role for early microglial MMP-9 expression in CNV, and furthermore that modulating microglial MMP expression is a novel putative therapeutic for CNV.
Highlights
Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly (Gehrs et al, 2006)
Active matrix metalloproteinases (MMPs)-9 (Figure 1B, left panel) and active MMP-2 (Figure 1C, left panel) levels were increased in the neovascular AMD group relative to control
In the retinal pigment epithelium (RPE)/choroid, the band intensities of pro-MMP-9 and active MMP-9 dramatically increased 6 h after choroidal neovascularization (CNV) induction, which was maintained through Day 1, followed by a subsequent decrease of active MMP-9 to basal levels by Day 3 post-CNV induction (Figure 2C)
Summary
Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly (Gehrs et al, 2006). For pathological angiogenesis to occur, the basement membrane surrounding endothelial tubes must be degraded to facilitate migration and proliferation of endothelial cells (Hanahan and Folkman, 1996), which is modulated in part by matrix metalloproteinases (MMPs; Pepper, 2001). Prior studies reported that in normal tissues, basal MMPs are absent or weakly expressed (Pepper, 2001). MMPs are upregulated in endothelial cells and immune cells in response to a variety of pathological events, including inflammation and angiogenesis (Lambert et al, 2002; O’Grady et al, 2007). Potential early changes of MMP expression prior to 3 days post-CNV, and the role of MMPs in initiation of the angiogenic response, have not been reported. The cell types that secrete active MMP-9 during early CNV formation have not been identified, which is paramount to the development of targeted approaches to treatment
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