Fig. 7.

Synergistic role of Rap1 isoforms in VEGFR2 signaling. Rap1 deficiency protects against increased retinal vascular permeability in the STZ-induced diabetes model. (A) Representative retinal flat-mounts from diabetic control, Rap1A-ECKO and Rap1B-ECKO mice injected with fluorescent dextran. Leakage is shown as hyperfluorescence extravasating from vessels. Scale bar: 50 μm. Quantification of fluorescent leakage, obtained from a single confocal slice, demonstrates reduced leakage in diabetic Rap1-ECKO mice compared with diabetic control mice (n≥8). (B) Proposed role of Rap1 isoforms in VEGF-mediated modulation of EC barrier function; a model built on current and published results. Rap1B, acting downstream from VEGFR2, is the predominant isoform responsible for VEGF-induced AJ dissociation and endothelial permeability, while both Rap1 isoforms promote full VEGFR2 activation and as such, participate in full response to VEGF. Rap1A is the main Rap1 isoform involved in structural maintenance of AJs, and its depletion may increase AJ susceptibility to VEGF-induced dissolution.