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-3β (GSK-3β) as a means for improving the architecture and functionality of pathological blood vessels in retina. In vitro, hypoxia increased GSK-3β activity in retinal endothelial cells, reduced β-catenin, and correspondingly impaired integrity of cell/cell junctions. Conversely, GSK-3β inhibitors restored β-catenin, improved cell/cell junctions, and enhanced the formation of capillary cords in three-dimensional collagen matrix. In vivo, GSK-3β 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-3β inhibitors offer a promising strategy for alleviating retinal hypoxia by correcting key vascular defects typically associated with ischemia-driven neovascularization.
Hoang
Mien V
MV
Department of Pathology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, 99 Brookline Avenue, Boston, MA 02215, USA.
Smith
Lois E H
LE
Senger
Donald R
DR
D000818:Animals; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D000860:Hypoxia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D007365:Intercellular Junctions / Q000187:drug effects / Q000378:metabolism; D007511:Ischemia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009024:Morphogenesis / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D012039:Regional Blood Flow; D012160:Retina / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D015861:Retinal Neovascularization / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D014652:Vascular Diseases / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D051176:beta Catenin / Q000378:metabolism
D047428:Protein Kinase Inhibitors; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
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