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1 From the Vascular Biology Center, 2 Departments of Pharmacology and Toxicology, 3 Cellular Biology and Anatomy, and 4 Ophthalmology, Medical College of Georgia, Augusta Georgia; and 5 Department of Oral Biology, Indiana University, Indianapolis.
PURPOSE. To determine transforming growth factor (TGF) ß effects on matrix metalloproteinases (MMPs) as a potential cause of the blood–retinal barrier breakdown at the onset of angiogenesis. Previously, glial cells were shown to play a role in the angiogenesis process and to express the angiogenic regulating factor TGF-ß, which becomes active under hypoxia conditions. Here, the authors demonstrate that retinal endothelial cells express MMP-9 when treated with TGF-ß or cocultured with glial cells and that both TGF-ß and MMP-9 increase endothelial cell permeability.
METHODS. Primary cultures of bovine retinal endothelial (BRE) cells grown on porous membranes were treated with TGF-ß or purified MMP-9, and permeability changes were assayed. The amount and distribution of the tight junction protein occludin also was analyzed by immunocytochemistry and Western blotting. Cell extracts or conditioned media from TGF-ß–treated BRE cells and from glial cell–BRE cocultures were analyzed for MMP-9 content by substrate gel electrophoresis (zymography) or Western blotting.
RESULTS. Both TGF-ß and MMP-9 increased the permeability of BRE monolayers and reduced the levels of the junction protein occludin. The effect of MMP-9 on permeability was rapid, but the TGF-ß–induced permeability required longer incubation and was blocked by anti–TGF-ß and anti–MMP-9 antibodies as well as by TGF-ß latency-associated peptide. Zymography showed that MMP-9 activity, which was very low or absent in untreated BRE cultures, was dramatically increased by TGF-ß as well as by coculturing with either astrocytes or Müller glial cells. Anti–TGF-ß antibody blocked the TGF-ß effect, but not the coculture effect on MMP-9 production.
CONCLUSIONS. These data indicate a direct correlation between TGF-ß–induced MMP-9 activity and increased endothelial cell permeability. Moreover, endothelial cell production of MMP-9 is regulated by glial cells through expression of TGF-ß or by direct cell-to-cell contact. During retinal disease, glial cell production of active TGF-ß may contribute to breakdown of the blood–retinal barrier by stimulating endothelial cell MMP-9 production.
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