title: Moderate GSK-3β inhibition improves neovascular architecture, reduces vascular leakage, and reduces retinal hypoxia in a model of ischemic retinopathy.
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 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.
authors.affiliation: 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.
authors.forename: Mien V
authors.initials: MV
authors.lastname: Hoang
authors.forename: Lois E H
authors.initials: LE
authors.lastname: Smith
authors.forename: Donald R
authors.initials: DR
authors.lastname: Senger
mesh_terms: 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
chemical_list: 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
references.citation: J Med Chem. 2002 Mar 14;45(6):1292-9
references.pmid: 11881998
references.citation: Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):1874-9
references.pmid: 14769914
references.citation: J Pharmacol Exp Ther. 2003 Jun;305(3):974-80
references.pmid: 12626660
references.citation: Arch Ophthalmol. 2003 Apr;121(4):547-57
references.pmid: 12695252
references.citation: Methods Mol Biol. 2005;294:269-85
references.pmid: 15576918
references.citation: Br J Ophthalmol. 1998 May;82(5):561-8
references.pmid: 9713066
references.citation: Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):905-9
references.pmid: 7846076
references.citation: J Mol Cell Cardiol. 2006 Jan;40(1):138-47
references.pmid: 16288908
references.citation: Mol Med. 1995 Jan;1(2):182-93
references.pmid: 8529097
references.citation: Proc Natl Acad Sci U S A. 1996 May 14;93(10):4851-6
references.pmid: 8643492
references.citation: Circ Res. 2005 Feb 18;96(3):308-18
references.pmid: 15662032
references.citation: J Biol Chem. 2003 Jan 3;278(1):327-34
references.pmid: 12399469
references.citation: Microvasc Res. 1993 Sep;46(2):135-42
references.pmid: 7504160
references.citation: Angiogenesis. 2007;10(2):133-40
references.pmid: 17332988
references.citation: Curr Opin Drug Discov Devel. 2008 Jul;11(4):533-43
references.pmid: 18600569
references.citation: Nat Rev Drug Discov. 2004 Jun;3(6):479-87
references.pmid: 15173837
references.citation: J Cell Sci. 2003 Apr 1;116(Pt 7):1175-86
references.pmid: 12615961
references.citation: Cardiovasc Res. 2008 Dec 1;80(3):354-64
references.pmid: 18689794
references.citation: J Biol Chem. 2010 May 14;285(20):15500-15510
references.pmid: 20231273
references.citation: J Cell Physiol. 2000 Sep;184(3):301-10
references.pmid: 10911360
references.citation: J Biol Chem. 2002 Nov 1;277(44):41667-73
references.pmid: 12200436
references.citation: Exp Cell Res. 2006 Mar 10;312(5):538-48
references.pmid: 16310771
references.citation: Am J Pathol. 2002 Jan;160(1):195-204
references.pmid: 11786413
references.citation: Cell Mol Life Sci. 2007 Aug;64(15):1930-44
references.pmid: 17530463
references.citation: Invest Ophthalmol Vis Sci. 1994 Jan;35(1):101-11
references.pmid: 7507904
references.citation: J Biol Chem. 2002 Nov 1;277(44):41888-96
references.pmid: 12167628
references.citation: Lab Invest. 1995 Jun;72(6):638-45
references.pmid: 7540233
references.citation: J Biol Chem. 2003 Nov 14;278(46):45937-45
references.pmid: 12928438
references.citation: Nat Med. 1999 Dec;5(12):1390-5
references.pmid: 10581081
references.citation: Nature. 2005 Dec 15;438(7070):960-6
references.pmid: 16355161
references.citation: Am J Pathol. 1994 Sep;145(3):574-84
references.pmid: 7521577
references.citation: Nat Med. 2007 Jul;13(7):868-873
references.pmid: 17589522
references.citation: N Engl J Med. 2004 Jan 1;350(1):48-58
references.pmid: 14702427