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Heidrun L. Deissler, Gabriele E. Lang; Ranibizumab Completely Reverts Barrier Malfunction Induced By Combination Of VEGF And Other Growth Factors. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3562.
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Growth factors like VEGF, PlGF, bFGF and IGF-1 are elevated in diabetic macular edema (DME). VEGF165 increases permeability of retinal endothelial cells (REC) after long term treatment which is strongly associated with loss of the tight junction (TJ) protein Claudin-1 and can be restored by VEGF inhibitor ranibizumab. To determine the VEGF receptor(s) involved in these processes, we studied whether VEGF-E or PlGF can induce these changes. In addition, we also investigated the influence of PlGF, bFGF or IGF-1 on the effect of VEGF165 and whether these were restored by ranibizumab.
Influence of growth factors on transendothelial resistance (TER) of immortalized bovine REC (iBREC) was measured over several days. Expression of Claudin-1, as an additional indicator of functional TJ, was assessed by Western blot analyses and immunofluorescence staining.
Whereas less than 50 ng/ml VEGF165, VEGF121 or VEGF-E was sufficient to significantly reduce TER or expression of Claudin-1 after treatment of iBREC for 2 days, PlGF, bFGF or IGF-1 (10 to 100 ng/ml) had no effect. Additive effects of VEGF165 by either VEGF121 or PlGF were not observed. However, changes in Claudin-1 expression or TER induced by 25 ng/ml VEGF165, were weakly enhanced by bFGF plus IGF-1 which was accompanied by slightly increased secretion of VEGF. Reduction of TER induced by VEGF in combination with IGF-1, bFGF or PlGF also correlated with loss of Claudin-1 and with reduced Claudin-3 expression at the plasma membrane. Expression of other TJ proteins (Claudin-5, ZO-1) was not affected. Complete reversion of reduced TER or Claudin-1 (Claudin-3) expression was achieved by ranibizumab when iBREC had been treated with 25 ng/ml VEGF165 together with PlGF or with bFGF and/or IGF-1 for 2 days.
Whereas activation of VEGF receptor 2 (or neuropilin) by VEGF-E is sufficient to induce elevated permeability in iBREC, activation of VEGF receptor 1 by PlGF is not. In addition, VEGF165 and/or VEGF121, but not IGF-1 or bFGF seem to be mainly responsible for changes in cellular permeability observed in REC. This supports VEGF targeting as a therapeutic concept for DME.
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