Moderate GSK-3β inhibition improves neovascular architecture, reduces vascular leakage, and reduces retinal hypoxia in a model of ischemic retinopathy

In ischemic retinopathies, unrelieved hypoxia induces the formation of architecturally abnormal, leaky blood vessels that damage retina and ultimately can cause blindness. Because these newly formed blood vessels are functionally defective, they fail to alleviate underlying hypoxia, resulting in more pathological neovascularization and more damage to retina. With an established model of ischemic retinopathy, we investigated inhibition of glycogen synthase kinase-3 beta (GSK-3 beta) as a means for improving the architecture and functionality of pathological blood vessels in retina. In vitro, hypoxia increased GSK-3 beta activity in retinal endothelial cells, reduced beta-catenin, and correspondingly impaired integrity of cell/cell junctions. Conversely, GSK-3 beta inhibitors restored beta-catenin, improved cell/cell junctions, and enhanced the formation of capillary cords in three-dimensional collagen matrix. In vivo, GSK-3 beta inhibitors, at appropriately moderate doses, strongly reduced abnormal vascular tufts, reduced abnormal vascular leakage, and improved vascular coverage and perfusion during the proliferative phase of ischemia-driven retinal neovascularization. Most importantly, these improvements in neovasculature were accompanied by marked reduction in retinal hypoxia, relative to controls. Thus, GSK-3 beta inhibitors offer a promising strategy for alleviating retinal hypoxia by correcting key vascular defects typically associated with ischemia-driven neovascularization.