title: Hypoxic retinal Muller cells promote vascular permeability by HIF-1-dependent up-regulation of angiopoietin-like 4.
abstract: Vision loss from ischemic retinopathies commonly results from the accumulation of fluid in the inner retina [macular edema (ME)]. Although the precise events that lead to the development of ME remain under debate, growing evidence supports a role for an ischemia-induced hyperpermeability state regulated, in part, by VEGF. Monthly treatment with anti-VEGF therapies is effective for the treatment of ME but results in a major improvement in vision in a minority of patients, underscoring the need to identify additional therapeutic targets. Using the oxygen-induced retinopathy mouse model for ischemic retinopathy, we provide evidence showing that hypoxic Müller cells promote vascular permeability by stabilizing hypoxia-inducible factor-1α (HIF-1α) and secreting angiogenic cytokines. Blocking HIF-1α translation with digoxin inhibits the promotion of endothelial cell permeability in vitro and retinal edema in vivo. Interestingly, Müller cells require HIF--but not VEGF--to promote vascular permeability, suggesting that other HIF-dependent factors may contribute to the development of ME. Using gene expression analysis, we identify angiopoietin-like 4 (ANGPTL4) as a cytokine up-regulated by HIF-1 in hypoxic Müller cells in vitro and the ischemic inner retina in vivo. ANGPTL4 is critical and sufficient to promote vessel permeability by hypoxic Müller cells. Immunohistochemical analysis of retinal tissue from patients with diabetic eye disease shows that HIF-1α and ANGPTL4 localize to ischemic Müller cells. Our results suggest that ANGPTL4 may play an important role in promoting vessel permeability in ischemic retinopathies and could be an important target for the treatment of ME.
authors: Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
authors: Xiaoban
authors: X
authors: Xin
authors: Murilo
authors: M
authors: Rodrigues
authors: Mahaa
authors: M
authors: Umapathi
authors: Fabiana
authors: F
authors: Kashiwabuchi
authors: Tao
authors: T
authors: Ma
authors: Savalan
authors: S
authors: Babapoor-Farrokhran
authors: Shuang
authors: S
authors: Wang
authors: Jiadi
authors: J
authors: Hu
authors: Imran
authors: I
authors: Bhutto
authors: Derek S
authors: DS
authors: Welsbie
authors: Elia J
authors: EJ
authors: Duh
authors: James T
authors: JT
authors: Handa
authors: Charles G
authors: CG
authors: Eberhart
authors: Gerard
authors: G
authors: Lutty
authors: Gregg L
authors: GL
authors: Semenza
authors: Silvia
authors: S
authors: Montaner
authors: Akrit
authors: A
authors: Sodhi
mesh_terms: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002199:Capillary Permeability; D015687:Cell Hypoxia; D002478:Cells, Cultured; D003930:Diabetic Retinopathy / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D007511:Ischemia / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D055351:Retinal Neurons / Q000166:cytology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A
keywords: angiogenesis; diabetes; retinal vein occlusion; transcription factor
references: FEBS J. 2011 Feb;278(4):559-64
references: 21182596
references: PLoS One. 2008;3(11):e3554
references: 18978936
references: Nature. 1996 Apr 4;380(6573):439-42
references: 8602242
references: Curr Opin Ophthalmol. 2011 May;22(3):185-9
references: 21427573
references: Hepatology. 2011 Sep 2;54(3):910-9
references: 21674552
references: Physiology (Bethesda). 2004 Aug;19:176-82
references: 15304631
references: Int J Biochem Cell Biol. 2009 Dec;41(12):2368-71
references: 19646547
references: Mol Vis. 2004 Jun 03;10:366-75
references: 15205663
references: FASEB J. 2010 Jun;24(6):1759-67
references: 20065104
references: Cell. 2008 Apr 4;133(1):66-77
references: 18394990
references: Neurol Res. 2012 May;34(4):325-30
references: 22643075
references: Acta Ophthalmol. 2009 Jun;87(4):362-7
references: 19416114
references: Biosci Rep. 2012 Jun;32(3):211-9
references: 22458843
references: FASEB J. 2010 Dec;24(12):4648-59
references: 20667978
references: Mol Cancer Ther. 2009 May;8(5):1148-56
references: 19435875
references: Clin Immunol. 2005 Apr;115(1):93-101
references: 15870027
references: J Biol Chem. 2011 Oct 21;286(42):36841-51
references: 21832056
references: Histopathology. 2011 Sep;59(3):470-81
references: 22034887
references: Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14363-8
references: 20660728
references: Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19579-86
references: 19020076
references: BMC Dev Biol. 2011 Oct 14;11:60
references: 21999428
references: Ophthalmologica. 2012;227 Suppl 1:21-9
references: 22517122
references: Circ Res. 2006 Nov 24;99(11):1207-15
references: 17068295
references: Invest Ophthalmol Vis Sci. 2002 May;43(5):1610-5
references: 11980881
references: Exp Physiol. 2005 Nov;90(6):791-7
references: 16157658
references: Curr Opin Endocrinol Diabetes Obes. 2012 Apr;19(2):93-6
references: 22262000
references: Curr Diabetes Rev. 2009 Feb;5(1):8-13
references: 19199892
references: Nat Rev Mol Cell Biol. 2004 May;5(5):343-54
references: 15122348
references: Circ Res. 2003 Nov 28;93(11):1074-81
references: 14576200
references: Oncol Rep. 2010 Sep;24(3):599-606
references: 20664963
references: Oncogene. 2012 Apr 5;31(14):1757-70
references: 21860410
references: PLoS One. 2010 Jun 14;5(6):e11103
references: 20559438
references: Invest Ophthalmol Vis Sci. 2004 May;45(5):1544-52
references: 15111613
references: Trends Cardiovasc Med. 2008 Jan;18(1):6-14
references: 18206803
references: Cell. 2012 Feb 3;148(3):399-408
references: 22304911
references: FASEB J. 2009 Mar;23(3):940-9
references: 19019854
references: Curr Opin Genet Dev. 2010 Feb;20(1):51-6
references: 19942427
references: Am J Physiol Endocrinol Metab. 2008 Nov;295(5):E1056-64
references: 18728224
references: Invest Ophthalmol Vis Sci. 2002 Mar;43(3):864-9
references: 11867609
references: Invest Ophthalmol Vis Sci. 1994 Jan;35(1):101-11
references: 7507904
references: Blood. 2011 Oct 6;118(14):3990-4002
references: 21841165
references: Eur J Ophthalmol. 2011;21 Suppl 6:S10-9
references: 23264324
references: Ophthalmology. 2011 Mar;118(3):548-52
references: 20920828
references: Arterioscler Thromb Vasc Biol. 2008 May;28(5):835-40
references: 18340008
references: Am J Pathol. 2003 May;162(5):1521-8
references: 12707035
references: Cancer Res. 2003 Oct 15;63(20):6651-7
references: 14583458
references: Dev Dyn. 2006 Dec;235(12):3336-47
references: 17061263
references: Nat Rev Mol Cell Biol. 2009 Mar;10(3):165-77
references: 19234476
references: Int J Hematol. 2012 May;95(5):464-70
references: 22539362
references: Semin Ophthalmol. 2009 Mar-Apr;24(2):52-61
references: 19373687
references: Angiogenesis. 2008;11(2):109-19
references: 18293091
references: Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18721-6
references: 17130448
references: Cancer Cell. 2003 Jan;3(1):23-36
references: 12559173
references: Expert Rev Proteomics. 2012 Apr;9(2):181-99
references: 22462789
references: Oncol Rep. 2011 Apr;25(4):929-35
references: 21308352
references: Exp Diabetes Res. 2012;2012:548732
references: 22474425