Abstract
Purpose: :
In a previous study we showed that MAPK signaling plays a key role in retinal angiogenesis, and that inhibition of the MAPK pathways by anthrax lethal toxin (LeTx) can profoundly alter vascular morphogenesis (Bromberg-White et. al. [2009] PLoS One, e6956). The goal of this study is to determine the role of MAPK signaling in the development and progression of retinal neovascularization, utilizing a mouse model of oxygen-induced retinopathy.
Methods: :
The pattern and cell-specificity of MAPK activation was analyzed during oxygen-induced retinopathy and subsequent development of neovascularization by immunoblotting and immunofluorescent imaging of retinal whole mounts. To assess the role of MAPK activation during oxygen-induced retinopathy, LeTx was injected intravitreally on return to a normoxic environment and subsequent effects on vascularization, vaso-obliteration, and neovascularzation were observed.
Results: :
Western analysis revealed that MAPK activation preceded the development of neovascularization following oxygen-induced retinopathy. Furthermore, active MAPK was associated with a non-endothelial cell compartment, presumably inflammatory cells such as macrophages. Lethal toxin administration following oxygen-induced retinopathy resulted in a marked delay in the development of retinal neovascularization as well as a complete inhibition in the revascularization of vaso-obliterated regions of the retina.
Conclusions: :
These results suggest that MAPK signaling pathways are activated in response to hypoxic insult following oxygen-induced retinopathy, and that MAPK activation is associated with a non-endothelial cell compartment. Furthermore, inhibition of MAPK signaling by LeTx indicates that MAPK pathways play a crucial role in the development and progression of retinal neovascularization following oxygen-induced retinopathy.
Keywords: retinal neovascularization • signal transduction • hypoxia