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H. Lei, G. Velez, A. Kazlauskas; Indirect Activation of PDGF Receptor Alpha Engages a PI3k/Akt/p53-Dependent Pathway That Promotes Cellular Responses Intrinsic to PVR. Invest. Ophthalmol. Vis. Sci. 2010;51(13):6084.
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© ARVO (1962-2015); The Authors (2016-present)
Proliferative vitreoretinopathy (PVR) is the primary cause of failure of retinal reattachment surgery. Platelet-derived growth factor (PDGF) receptor alpha (PDGFRα) plays a key role in experimental PVR and is also implicated in clinical PVR. While PDGFs that activate PDGFRα abound in the vitreous, they are not required for experimental PVR. Furthermore, vitreal growth factors outside of the PDGF family indirectly activate PDGFRα, and this mechanism of PDGFRα activation is sufficient to induce PVR. The goal of this study was to compare and contrast the signaling events emanating from directly and indirectly activated PDGFRα, and identify those signaling events that are essential for development of experimental PVR.
PDGFRα in retinal pigment epithelial cells or fibroblasts was activated directly (with PDGF) or indirectly (with vitreous or growth factors outside of the PDGF family). Activation of PDGFRα, Akt and Mdm2 was monitored by Western blot analysis using phosphotyrosine or phospho-specific antibodies. Cell number was assessed to measure proliferation; expression of cell surface annexin V was monitored to indicate apoptosis.
There was at least a 4 fold difference in the half-life of directly and indirectly activated PDGFRα: less than 30 min and greater than 120 min, respectively. Both modes of activating PDGFRα engaged the phosphoinositide 3 kinase (PI3K)/Akt pathway, which was essential for experimental PVR. In response to indirect activation of PDGFRα, PI3K/Akt activation was prolonged and resulted in increased phosphorylation of Mdm2, a decline in the level of p53, enhanced proliferation and survival of cells. In contrast, direct activation of PDGFRα resulted in transient activation of PI3K/Akt and only a slight decline in p53 that only modestly impacted proliferation or survival of cells.
The mode of activation of PDGFRα influenced the duration of subsequent intracellular signaling events and their consequences. These studies improve our understanding of the pathogenesis of PVR and thereby set the stage to develop effective approaches to prevent it.
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