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D. A. Antonetti, T. Murakami, E. Wolpert, K. Gonsar, E. Felinski; Regulation of VEGF Induced Endothelial Permeability. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3642.
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© ARVO (1962-2015); The Authors (2016-present)
Normally, the well-developed tight junctions of the retinal vasculature convey strict control of endothelial permeability. Growth factors VEGF and FGF induce vascular permeability in a number of retinal eye diseases including retinopathy of prematurity, diabetic retinopathy, and age related macular degeneration. Our laboratory has investigated the signaling mechanisms by which VEGF alters the junctional complex and induces endothelial permeability. Previously, we have shown that classical PKC isoforms including PKCbeta are responsible for part of the VEGF induced increase in permeability. Here we demonstrate that the atypical PKC isoform, PKCzeta, also contributes to VEGF and FGF induced permeability.
Primary cultures of bovine retinal endothelial cells were grown on transwell filters for permeability studies. The myristoylated PKCzeta peptide inhibitor was used to inhibit enzyme activity. PKCzeta activity was assessed by Western blot for phospho-protein.
VEGF and FGF induce endothelial permeability in BREC and act additively. Both growth factors induce PKCzeta activation as determined by phospho-PKCzeta blotting. Inhibition of PKCzeta prevented VEGF induced endothelial permeability to 70kDa RITC-dextran in a dose dependent manner. Transfection of BREC with PKCzeta had no effect on basal permeability but augmented VEGF induced endothelial permeability. Finally, Ser490 and Thr168 have been identified as phospho-sites on occludin that conform to PKCzeta consensus sequences.
VEGF signaling through PKCzeta contributes to endothelial permeability. Targeting PKCzeta may augment current therapeutic strategies directed to PKCbeta and may provide more complete control of vascular permeability. Finally, occludin is a potential downstream target of PKCzeta that may contribute to the regulation of endothelial permeability.
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