Activin a in the regulation of corneal neovascularization and vascular endothelial growth factor expression.
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.
Poulaki
Vassiliki
V
Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, and the Dana Faber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Mitsiades
Nicholas
N
Kruse
Friedrich E
FE
Radetzky
Sven
S
Iliaki
Eirini
E
Kirchhof
Bernd
B
Joussen
Antonia M
AM
D028341:Activins / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D003315:Cornea / Q000098:blood supply*; D065306:Corneal Injuries; D016510:Corneal Neovascularization / Q000503:physiopathology*; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000502:physiology; D006801:Humans; D028322:Inhibin-beta Subunits / Q000378:metabolism*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D048051:p38 Mitogen-Activated Protein Kinases
D042461:Vascular Endothelial Growth Factor A; C422405:activin A; D028341:Activins; D028322:Inhibin-beta Subunits; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases