Activin A in the Regulation of Corneal Neovascularization and Vascular Endothelial Growth Factor Expression

Abstract

Activin A, a dimeric glycoprotein that belongs to the transforming growth factor-beta superfamily, governs cellular differentiation in a wide variety of models and has been implicated in the regulation of angiogenesis. We examined the role of activin A and its downstream signaling pathway in a murine model of inflammatory corneal neovascularization induced by mechanical injury (debridement), and in vitro in corneal epithelial cells. Activin A expression increased steadily from day 2 until day 8 after mechanical debridement in vivo, paralleling vascular endothelial growth factor (VEGF) expression. Administration of recombinant activin A in mice increased the area of neovascularization, VEGF expression, and the kinase activities of p38 and p42/44 MAPKs after mechanical debridement. Systemic inhibition of activin A in vivo with a neutralizing antibody reduced the area of neovascularization, VEGF expression, and p38 and p42/44 MAPK activity, whereas administration of an isotype-matched control antibody had no effect. In vitro treatment with activin A increased VEGF secretion, as well as p38 and p42/44 MAPK activity in corneal epithelial cells, whereas concurrent administration of specific inhibitors of p38 or p42/44 MAPK abolished the stimulatory effect of activin A on VEGF production. We conclude that activin A stimulates inflammatory corneal angiogenesis by increasing VEGF levels through a p38 and p42/44 MAPK-dependent mechanism.