Moderate GSK3β inhibition improves neovascular ar

Authors: Mien V Hoang Lois E H Smith Donald R Senger

Publish Date: 2010/09/01

Volume: 13, Issue: 3, Pages: 269-277

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Abstract

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 kinase3β GSK3β as a means for improving the architecture and functionality of pathological blood vessels in retina In vitro hypoxia increased GSK3β activity in retinal endothelial cells reduced βcatenin and correspondingly impaired integrity of cell/cell junctions Conversely GSK3β inhibitors restored βcatenin improved cell/cell junctions and enhanced the formation of capillary cords in threedimensional collagen matrix In vivo GSK3β 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 ischemiadriven retinal neovascularization Most importantly these improvements in neovasculature were accompanied by marked reduction in retinal hypoxia relative to controls Thus GSK3β inhibitors offer a promising strategy for alleviating retinal hypoxia by correcting key vascular defects typically associated with ischemiadriven neovascularizationWe thank the V Kann Rasmussen Foundation for financial support This work also was supported by NIH grants CA129339 and NS064498 DRS NIH grants EY017017 and EY017017S LEHS The Roche Foundation for Anemia Research LEHS and a Research to Prevent Blindness Senior Investigator Award LEHS

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