The role of VIP family members in diabetic retinopathy

Diabetic retinopathy (DR) is a microvascular complication of diabetes leading to blindness. Hyperglycemic/hypoxic microenvironment concurs to mechanical breakdown of blood-retinal barrier (BRB) as well as the aberrant angiogenesis activating many downstream target genes including inflammatory cytokines and vasoactive peptides, such as interleukin-1beta and vascular endothelial growth factor (VEGF). To date, intravitreal injection of agents directed against VEGF represents the elective DR therapy. However, they counteract efficaciently ocular neovascularization only in 50% of treated patients, suggesting that other pathogenic events may play an important role in non-responders. Therefore, there is an increased need for new molecule able to counteract microenvironmental alterations of DR. It has been largely demonstrated that pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) exert a protective effect against retinal injuries, including DR. However, until now, no study has investigated their protective role against the harmful combined effect of both hyperglycemia and hypoxia. The main objectives of this PhD thesis have been evaluate whether PACAP protects retinal tissue of diabetic rats through modulation of hypoxia and inflammation, both converging on angiogenic process. Moreover, we have investigated the protective effects of PACAP and VIP on BRB integrity whose breakdown due to hypoxic and inflammatory event, leads to diabetic macular edema (DME). The results have demonstrated that a single intravitreal administration of PACAP in streptozotocin-injected rats modulated the expression of hypoxic, inflammatory and angiogenic factors. Moreover, PACAP and VIP restored the integrity of BRB through the activation of phosphoinositide 3 kinase (PI3K)/Akt and mammalian mitogen activated protein kinase/Erk kinase (MAPK/ERK) survival signaling pathways. Overall, these data indicate that these peptides, both in vivo and in vitro, perform a beneficial effect to attenuate some pathologic events occuring in DR.