Fig. 6.

Hypoxia-mediated repression of EPAC-1 by microRNA-7 in retinopathy. Schematic representation of the study outcomes. Hypoxia during retinopathy increases the expression of microRNA-7, which in turn reduces the protein availability of EPAC-1. The loss of EPAC-1 in endothelial cells causes endothelial junctional instability and concurrently hyperpermeability, as well as the loss of eNOS expression and eNOS activity, resulting in oxidative stress. Combined, hyperpermeability and oxidative stress might further reduce the oxygen transport creating a feed-forward mechanism that aggravates retinopathy. Stimulators of cAMP signaling and EPAC-1 efficiently activate the remnant EPAC-1 protein, which antagonizes the hypoxia-induced damage. Therefore, EPAC-1 is an appropriate drugable target for the treatment of endothelial dysfunction during (diabetic) retinopathy