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S Radetzky, AM Joussen, B Kirchhof, V Poulaki; Activin A Stimulates Inflammatory Corneal Neovascularization . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1862.
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Purpose: Activin A is a dimeric glycoprotein that belongs to the transforming growth factor beta (TGF-beta) superfamily and is involved in the pathogenesis of proliferative membrane formation in both ischemic and nonischemic vitreoretinal diseases. We examined the role of activin A in inflammatory corneal neovascularization. Method: Corneal neovascularization was induced in vivo by a mechanical debridement of the corneal and limbal epithelium with 0.15 M NaOH in C57BL6 mice. Activin A and VEGF corneal protein levels were measured 4, 5 and 8 days later with an ELISA assay. The activities of the p38 and p42/44 kinases were measured on day 7. To investigate the effect of activin A on inflammatory corneal neovascularization and VEGF expression, we implanted mice with osmotic pumps containing either recombinant activin A, or a neutralizing antibody against activin A. The area of neovascularization was quantified on day 7. The direct effects of activin A on VEGF expression were investigated in vitro in corneal epithelial and microvascular endothelial cells. Results: Activin A expression increased steadily from day 4 until day 8 after the mechanical debridement, paralleling VEGF expression. Administration of activin A in mice increased the area of neovascularization, VEGF expression and the kinase activities of p38 and p42/44 MAPKs. Systemic inhibition of activin A in vivo reduced the area of neovascularization, VEGF expression and p38 and p42/44 MAPK activity. In vitro treatment with activin A increased VEGF secretion, as well as p38 and p42/44 MAPK activity in corneal epithelial and microvascular endothelial cells, whereas concurrent administration of specific inhibitors of p38 or p42/44 MAPK abolished the stimulatory effect of activin A on VEGF production. Conclusion: Activin A stimulates inflammatory corneal angiogenesis by increasing VEGF levels through a p38 and p42/44 MAPK-dependent mechanism.
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