Abstract
Epigalloccatechin-3-gallate (EGCG) is the main polyphenol component of green tea (leaves of Camellia sinensis). EGCG is known for its antioxidant, anti-inflammatory, antiviral, and anti-carcinogenic properties. Here, we identify EGCG as a new inhibitor of ocular angiogenesis and its vascular permeability. Matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) play a key role in the processes of extracellular matrix (ECM) remodeling and microvascular permeability during angiogenesis. We investigated the inhibitory effects of EGCG on ocular neovascularization and vascular permeability using the retina oriented cells and animal models induced by VEGF and alkaline burn. EGCG treatment significantly decreased mRNA and protein expression levels of MMP-9 in the presence of 12-O-tetradecanoylphorbol-13-acetate (TPA) and tumor necrosis factor alpha (TNF-α) in human retinal pigment epithelial cells (HRPECs). EGCG also effectively protected ARPE-19 cells from cell death and attenuated mRNA expressions of key angiogenic factors (MMP-9, VEGF, VEGF Receptor-2) by inhibiting generation of reactive oxygen species (ROS). EGCG significantly inhibited proliferation, vascular permeability, and tube formation in VEGF-induced human retinal microvascular endothelial cells (HRMECs). Furthermore, EGCG significantly reduced vascular leakage and permeability by blood-retinal barrier breakdown in VEGF-induced animal models. In addition, EGCG effectively limited upregulation of MMP-9 and platelet endothelial cell adhesion molecule (PECAM/CD31) on corneal neovascularization (CNV) induced by alkaline burn. Our data suggest that MMP-9 and VEGF are key therapeutic targets of EGCG for treatment and prevention of ocular angiogenic diseases such as age-related macular degeneration, diabetic retinopathy, and corneal neovascularization.
Highlights
Neovascularization is the process of formation of new capillary vessels from preexisting blood vessels
We show for the first time that EGCG protects human retina cells against blood–retinal barrier (BRB) alteration, ocular neovascularization, and vascular permeability via suppression of Matrix metalloproteinases (MMPs)-9 and the consequent vascular endothelial growth factor (VEGF) activation in retinal pigment epithelium (RPE) and retinal microvascular endothelial (RME) cells
To examine whether EGCG induces a cytotoxic effect in RPE and RME cells, we evaluated cell viability at doses ranging from 1 to 100 μM EGCG
Summary
Neovascularization is the process of formation of new capillary vessels from preexisting blood vessels. New capillary vessels arise from the pericorneal plexus and sprout into the stroma [13,14] Key mediators such as VEGF, bFGF, and matrix metalloproteinases (MMPs) are known to play an important role in this process [15]. EGCG was found to decrease VEGF receptor phosphorylation in human umbilical arterial endothelial cells (HUAECs) and has been reported to inhibit the MMP-2 and MMP-9 in human umbilical vein endothelial cells (HUVECs) [30,31] Whether these angiogenic factors, including VEGF and ECM-related molecules, play an important role in RPE and retinal microvascular endothelial (RME) cells, and the precise mechanism by which they do so, is unclear. We show for the first time that EGCG protects human retina cells against BRB alteration (breakdown and remodeling), ocular neovascularization, and vascular permeability via suppression of MMP-9 and the consequent VEGF activation in RPE and RME cells
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