Increased
retinal vasopermeability contributes to
diabetic retinopathy, the leading cause of
blindness in working-age adults. Despite clinical progress, effective
therapy remains a major need. Vasoinhibins, a family of
peptides derived from the
protein hormone prolactin (and inclusive of the 16-kDa fragment of
prolactin), antagonize the proangiogenic effects of
VEGF, a primary mediator of
retinal vasopermeability. Here, we demonstrate what we believe to be a novel function of vasoinhibins as inhibitors of the increased
retinal vasopermeability associated with
diabetic retinopathy. Vasoinhibins inhibited
VEGF-induced vasopermeability in bovine aortic and rat
retinal capillary endothelial cells in vitro. In vivo, vasoinhibins blocked
retinal vasopermeability in diabetic rats and in response to intravitreous injection of
VEGF or of vitreous from patients with
diabetic retinopathy. Inhibition by vasoinhibins was similar to that achieved following immunodepletion of
VEGF from human
diabetic retinopathy vitreous or blockage of NO synthesis, suggesting that vasoinhibins inhibit
VEGF-induced NOS activation. We further showed that vasoinhibins activate
protein phosphatase 2A (PP2A), leading to eNOS dephosphorylation at Ser1179 and, thereby, eNOS inactivation. Moreover, intravitreous injection of
okadaic acid, a PP2A inhibitor, blocked the vasoinhibin effect on endothelial cell permeability and
retinal vasopermeability. These results suggest that vasoinhibins have the potential to be developed as new therapeutic agents to control the excessive
retinal vasopermeability observed in
diabetic retinopathy and other vasoproliferative retinopathies.