MMP-2 and MMP-9 Secretion by Rpe Is Stimulated by Angiogenic Molecules Found in Choroidal Neovascular Membranes

Stephan, Holger; He, Shikun; Ehren, Marianne; Ryan, Stephen J.; Wiedemann, Peter; Hinton, David R.

doi:10.1097/00006982-200604000-00012

Cited by 40 publications

(27 citation statements)

References 43 publications

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“…20 -22 The retinal pigment epithelium (RPE) expresses both MMP-2 and MMP-9, 26 and it has been shown that growth factors and inflammatory mediators upregulate the expression of MMPs in RPE cells. [27][28][29] In experimental CNV, the upregulation of MMP-9 has especially been associated with neovascularization. 24 Whereas the normal healthy retina of the mouse displays no or weak expression of MMP-9, MMP-9 is increasingly expressed in the vicinity of laser-induced retinal injury, in the RPE and choroidea, and in inflammatory cells.…”

Section: Resultsmentioning

confidence: 99%

Positive Feedback Regulation between MMP-9 and VEGF in Human RPE Cells

Hollborn

Stathopoulos

Steffen

et al. 2007

Invest. Ophthalmol. Vis. Sci.

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154

114

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Section: Resultsmentioning

confidence: 99%

Positive Feedback Regulation between MMP-9 and VEGF in Human RPE Cells

Hollborn

Stathopoulos

Steffen

et al. 2007

Invest. Ophthalmol. Vis. Sci.

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154

114

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“…Conversely, VEGF can cause MMP release and activation. VEGF was reported to induce MMP-2 and MMP-9 secretion from RPE in vitro (Hoffmann et al, 2006). In addition, MMP activity was increased in microvascular endothelial cells exposed to VEGF (Lamoreaux et al, 1998).…”

Section: Extracellular Matrix Proteolysis and Vegf-proteolytic Enzymementioning

confidence: 94%

Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

636

527

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Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the U.S., for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Evidence suggests that vascular endothelial growth factor (VEGF), a 40 kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis.

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“…Recent studies indicate that MMP-2 is indispensable in forming CNV because reduced CNV or attenuated retinal angiogenesis are observed in MMP-2 deficient mice [8,9]. RPE is a major resource for producing MMP-2 in the retina and overexpression of VEGF and MMP-2 by RPE is critical for angiogenesis in CNV [10,11]. …”

Section: Introductionmentioning

confidence: 99%

Roles of NFκB-miR-29s-MMP-2 circuitry in experimental choroidal neovascularization

Cai

Yin

Lin

et al. 2014

J Neuroinflammation

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BackgroundPrevious reports have indicated that matrix metallopeptidase-2 (MMP-2) regulates angiogenic processes, which are involved in choroidal neovascularization (CNV). However, the regulation of MMP-2 in CNV has not been well-characterized. To gain more information about the regulation of MMP-2 in CNV, we analyzed the circuitry associated with MMP-2 regulation in a CNV model and in cell cultures, focusing on NFκB and the microRNA-29 family (miR-29s).MethodsThe CNV model was established by subjecting C57BL/6 mice to fundus photocoagulation with a krypton red laser. In choroidal-retinal pigment epithelial (RPE) tissues of the model, immunohistochemistry was used to evaluate the angiogenesis and MMP-2 expression; reverse-transcription quantitative PCR (RT-qPCR) was used to determine the levels of miR-29s; and western blot was used to analyze the protein levels of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) inhibitor, IκBα, and its phosphorylated form, phospho-IκBα. At the cellular level, RT-qPCR was used to examine the levels of miR-29s following NFκB activation by tumor necrosis factor alpha (TNFα); and western blot and luciferase assay were used to determine the regulation of MMP-2 by miR-29s in a human RPE cell line (ARPE-19) and in an umbilical vein endothelial cell line (EA hy926).ResultsMMP-2 staining was increased in the choroidal neovascular membrane of laser-treated retina. Also, the NFκB pathway was induced in choroid-RPE tissue, as evidenced by a lower protein level of IκBα and a higher level of phospho-IκBα in the tissue homogenates than in those from non-treated eyes. During the period when the NFκB pathway was induced, reduced miR-29s were detected in the choroidal-RPE tissue of the laser-treated eyes. In cultured ARPE-19 cells, TNFα decreased miR-29a, b, and c, and the effects were rescued by NFκB decoy. In ARPE-19 and EA hy926, miR-29s mimics reduced the contents of secreted MMP-2 in the culture media. We also documented that miR-29s reduced MMP-2 3’-UTR-mediated luciferase transcription.ConclusionsThe results suggest that in CNV, NFκB activation inhibits miR-29s, which may contribute to angiogenesis by up-regulating the MMP-2 protein level in RPE cells. These observations may help in developing a strategy for resolving CNV by targeting miR-29s levels.

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MMP-2 and MMP-9 Secretion by Rpe Is Stimulated by Angiogenic Molecules Found in Choroidal Neovascular Membranes

Abstract: The results indicated that the angiogenic molecules VEGF, FN, and TNF-alpha stimulate MMP-2 and -9 secretion from RPE and thus further promote CNV.

Cited by 40 publications

References 43 publications

Positive Feedback Regulation between MMP-9 and VEGF in Human RPE Cells

Positive Feedback Regulation between MMP-9 and VEGF in Human RPE Cells

Vascular endothelial growth factor in eye disease

Roles of NFκB-miR-29s-MMP-2 circuitry in experimental choroidal neovascularization

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