The PGF-induced effects on retinal vasculature could result from a direct Flt-1 activation, but also from the PGF-induced VEGF displacement from Flt-1 and sFlt-1 toward Flk-1, which is over-expressed in pathological conditions. Moreover, hetero-dimerization of PGF with VEGF could exert mitogenic effects on endothelial cells by activating inter- and intra-molecular interactions between both VEGF receptors. In addition, PGF indirectly stimulates angiogenesis by recruiting inflammatory cells, and so, by amplifying VEGF and pro-inflammatory cytokine production. Surprisingly, in our model, IL-1beta and TNF-alpha, which are among the more pro angiogenic inflammatory cytokines, were down regulated in the retina submitted to sustained PGF exposure. Indeed, PGF has been shown to trigger production of proinflammatory cytokines as TNF-alpha and IL-1beta in monocytes from patients with single cell SP600125 JNK inhibitor disease, as well as TNF-alpha and IL-6 in the synovial tissue from patient with rheumatoid inflammation. However, it has also been demonstrated that PGF modulates differentiation and maturation of dendritic cells in response to LPS, inhibiting NF-kappaB activity, and so inhibiting TNF-alpha production. These studies suggest that PGF effects depend on target cells and on their environment. Our model showed that, after two months of production, rPGF-1 maintained VEGF expression promotion, but significantly downregulated IL-1beta and TNF-alpha expression in retinal cells. This observation suggests that PGF may influence the cytokinic retinal micro-environment and may modulate the function of retinal inflammatory cells, as microglia. As IL-1beta and TNF-alpha are among the most pro-angiogenic inflammatory cytokines, their down-regulation may explain in part why no real vitreoretinal neovascularization occurred. On the other hand, a significant increase in IL-6 resulted from PGF over expression. The exact significance of this increase remains to be determined, as IL-6 can have pro or anti inflammatory effects. Withal, a recent clinical study showed that ten weeks after intravitreal injection of bevacizumab, a Navitoclax monoclonal antibody targeting VEGF, recurrence of edema occurred with low VEGF levels and high IL-6 levels in the aqueous humor, suggesting that PGF-induced IL-6 production may contribute to vascular permeability. The permeabilizing effect of PGF was also observed at the outer retinal barrier level, where disrupted occludin staining was observed at the tightjunctions together with changes in the morphology of RPE cells, suggesting alteration of this barrier, as previously described after acute PGF injection in the rat. In the early phases of DR, alterations of retinal capillaries and focal aneurismal deformations progressively develop, very similar to what was observed in retina exposed chronically to PGF or in retina from GK rats.