title: Stop the flow: a paradigm for cell signaling mediated by reactive oxygen species in the pulmonary endothelium.
abstract: The lung endothelium is exposed to mechanical stimuli through shear stress arising from blood flow and responds to altered shear by activation of NADPH (NOX2) to generate reactive oxygen species (ROS). This review describes the pathway for NOX2 activation and the downstream ROS-mediated signaling events on the basis of studies of isolated lungs and flow-adapted endothelial cells in vitro that are subjected to acute flow cessation (ischemia). Altered mechanical stress is detected by a cell-associated complex involving caveolae and other membrane proteins that results in endothelial cell membrane depolarization and then the activation of specific kinases that lead to the assembly of NOX2 components. ROS generated by this enzyme amplify the mechanosignal within the endothelial cell to regulate activation and/or synthesis of proteins that participate in cell growth, proliferation, differentiation, apoptosis, and vascular remodeling. These responses indicate an important role for NOX2-derived ROS associated with mechanotransduction in promoting vascular homeostasis.
authors.affiliation: Institute for Environmental Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. abf@mail.med.upenn.edu
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Browning
authors.forename: Shampa
authors.initials: S
authors.lastname: Chatterjee
authors.forename: Aron B
authors.initials: AB
authors.lastname: Fisher
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology*; D004727:Endothelium / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007473:Ion Channels / Q000502:physiology; D008168:Lung / Q000378:metabolism / Q000502:physiology*; D040542:Mechanotransduction, Cellular / Q000502:physiology; D008562:Membrane Glycoproteins / Q000502:physiology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism / Q000502:physiology; D011652:Pulmonary Circulation / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013314:Stress, Mechanical
chemical_list: D007473:Ion Channels; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
references.citation: Curr Opin Struct Biol. 2004 Dec;14(6):679-86
references.pmid: 15582391
references.citation: Am J Physiol Heart Circ Physiol. 2007 Feb;292(2):H954-62
references.pmid: 17028163
references.citation: J Biol Chem. 2011 Apr 1;286(13):11696-706
references.pmid: 21262967
references.citation: Physiol Rev. 1995 Jul;75(3):519-60
references.pmid: 7624393
references.citation: Am J Physiol Heart Circ Physiol. 2001 May;280(5):H2126-35
references.pmid: 11299214
references.citation: Antioxid Redox Signal. 2011 Aug 1;15(3):831-44
references.pmid: 20919932
references.citation: Curr Opin Neurobiol. 1995 Jun;5(3):268-77
references.pmid: 7580148
references.citation: Blood. 1999 Mar 1;93(5):1464-76
references.pmid: 10029572
references.citation: Biochem J. 2009 May 1;419(3):669-79
references.pmid: 19140803
references.citation: Am J Pathol. 2006 May;168(5):1749-61
references.pmid: 16651639
references.citation: Am J Physiol. 1998 Jan;274(1):C25-37
references.pmid: 9458709
references.citation: J Leukoc Biol. 2003 Apr;73(4):511-24
references.pmid: 12660226
references.citation: Mol Biol Cell. 2007 Jun;18(6):2002-12
references.pmid: 17360969
references.citation: Circ Res. 2003 Aug 22;93(4):354-63
references.pmid: 12893742
references.citation: Adv Drug Deliv Rev. 2009 Nov 30;61(14):1324-31
references.pmid: 19716389
references.citation: Antioxid Redox Signal. 2008 Apr;10(4):679-89
references.pmid: 18162054
references.citation: Circ Res. 1999 Oct 15;85(8):682-9
references.pmid: 10521241
references.citation: Free Radic Biol Med. 2005 Jun 15;38(12):1543-52
references.pmid: 15917183
references.citation: Free Radic Biol Med. 2009 Jan 15;46(2):146-53
references.pmid: 18973804
references.citation: Am J Physiol Lung Cell Mol Physiol. 2001 Oct;281(4):L993-1000
references.pmid: 11557603
references.citation: Am J Respir Cell Mol Biol. 1998 May;18(5):653-61
references.pmid: 9569235
references.citation: Circ Res. 1999 Oct 29;85(9):820-8
references.pmid: 10532950
references.citation: Am J Physiol Lung Cell Mol Physiol. 2010 Oct;299(4):L535-41
references.pmid: 20693319
references.citation: J Biol Chem. 2000 Sep 15;275(37):28421-7
references.pmid: 10893423
references.citation: Cardiovasc Res. 2005 Feb 1;65(2):495-504
references.pmid: 15639489
references.citation: Am J Physiol Cell Physiol. 2001 Jan;280(1):C216-27
references.pmid: 11121393
references.citation: Am J Physiol Cell Physiol. 2007 Jan;292(1):C82-97
references.pmid: 16870827
references.citation: J Biol Chem. 2000 Dec 22;275(51):39807-10
references.pmid: 11042195
references.citation: J Cell Biol. 2002 Aug 19;158(4):773-85
references.pmid: 12177047
references.citation: J Biol Chem. 2007 Jan 12;282(2):1183-92
references.pmid: 17105724
references.citation: J Biol Chem. 1998 Jan 2;273(1):441-5
references.pmid: 9417101
references.citation: Circ Res. 1981 Apr;48(4):481-8
references.pmid: 7460219
references.citation: Biotechnol Bioeng. 1988 Oct 5;32(8):1053-60
references.pmid: 18587822
references.citation: Free Radic Biol Med. 1997;23(1):47-56
references.pmid: 9165296
references.citation: Free Radic Biol Med. 2011 Jul 1;51(1):160-70
references.pmid: 21545835
references.citation: Am J Physiol Cell Physiol. 2003 Oct;285(4):C959-67
references.pmid: 12826604
references.citation: Arch Biochem Biophys. 1992 Jul;296(1):183-9
references.pmid: 1605629
references.citation: J Am Soc Nephrol. 2010 Apr;21(4):587-97
references.pmid: 20150534
references.citation: Annu Rev Physiol. 1997;59:171-91
references.pmid: 9074760
references.citation: IUBMB Life. 2004 Apr;56(4):185-91
references.pmid: 15230345
references.citation: J Thorac Cardiovasc Surg. 1998 Aug;116(2):294-304
references.pmid: 9699583
references.citation: Comp Biochem Physiol B Biochem Mol Biol. 1998 Jun;120(2):393-404
references.pmid: 9787801
references.citation: Semin Thromb Hemost. 2010 Apr;36(3):301-8
references.pmid: 20490980
references.citation: Exp Physiol. 2005 Jul;90(4):449-55
references.pmid: 15890798
references.citation: Antioxid Redox Signal. 2004 Apr;6(2):245-58
references.pmid: 15025926
references.citation: Antioxid Redox Signal. 2005 May-Jun;7(5-6):619-26
references.pmid: 15890005
references.citation: Arch Biochem Biophys. 2009 May 15;485(2):139-49
references.pmid: 19236840
references.citation: Antioxid Redox Signal. 2009 Apr;11(4):791-810
references.pmid: 18783313
references.citation: J Cell Physiol. 1996 Feb;166(2):274-80
references.pmid: 8591986
references.citation: Am J Physiol Heart Circ Physiol. 2005 Jan;288(1):H336-43
references.pmid: 15331375
references.citation: Antioxid Redox Signal. 1999 Summer;1(2):145-54
references.pmid: 11228743
references.citation: Biochim Biophys Acta. 2008 Oct;1783(10):1866-75
references.pmid: 18573285
references.citation: Free Radic Biol Med. 2009 Nov 1;47(9):1239-53
references.pmid: 19628035
references.citation: J Exp Med. 2000 Oct 2;192(7):1001-14
references.pmid: 11015441
references.citation: Am J Physiol. 1997 Feb;272(2 Pt 1):L294-300
references.pmid: 9124381
references.citation: Circ Res. 2003 Nov 14;93(10):e136-42
references.pmid: 14563712
references.citation: PLoS One. 2010 Apr 21;5(4):e10189
references.pmid: 20422004
references.citation: J Magn Reson Imaging. 2006 Dec;24(6):1386-92
references.pmid: 17083089
references.citation: Circ Res. 1998 Oct 5;83(7):730-7
references.pmid: 9758643
references.citation: Nature. 2003 Oct 30;425(6961):980-4
references.pmid: 14586471
references.citation: Annu Rev Physiol. 1997;59:527-49
references.pmid: 9074776
references.citation: J Cell Mol Med. 2003 Jan-Mar;7(1):57-66
references.pmid: 12767262
references.citation: Circ Res. 2002 Sep 6;91(5):406-13
references.pmid: 12215489
references.citation: Proc Natl Acad Sci U S A. 2002 May 28;99(11):7780-5
references.pmid: 12032360
references.citation: Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9462-7
references.pmid: 12080144
references.citation: Am J Physiol. 1995 Aug;269(2 Pt 1):L158-64
references.pmid: 7544536
references.citation: Antioxid Redox Signal. 2009 Apr;11(4):841-60
references.pmid: 18828698
references.citation: Mol Cell Biochem. 2002 May-Jun;234-235(1-2):49-62
references.pmid: 12162460
references.citation: Am J Physiol Lung Cell Mol Physiol. 2001 Sep;281(3):L529-33
references.pmid: 11504676
references.citation: Arterioscler Thromb Vasc Biol. 1997 Dec;17(12):3570-7
references.pmid: 9437207
references.citation: Am J Physiol Lung Cell Mol Physiol. 2005 Dec;289(6):L954-61
references.pmid: 16280460
references.citation: J Cell Biol. 2005 Sep 26;170(7):1079-90
references.pmid: 16186254
references.citation: Am J Physiol Cell Physiol. 2006 Jan;290(1):C66-76
references.pmid: 16107509
references.citation: Free Radic Biol Med. 1999 Aug;27(3-4):322-8
references.pmid: 10468205
references.citation: Am J Physiol. 1997 Dec;273(6):L1112-7
references.pmid: 9435564
references.citation: Nature. 1988 Jan 14;331(6152):168-70
references.pmid: 2448637
references.citation: Arterioscler Thromb Vasc Biol. 2010 Apr;30(4):653-61
references.pmid: 19910640
references.citation: Am J Physiol. 1995 Apr;268(4 Pt 2):H1765-72
references.pmid: 7733381
references.citation: FASEB J. 2009 Apr;23(4):1011-22
references.pmid: 19028840
references.citation: Am J Physiol Lung Cell Mol Physiol. 2004 Sep;287(3):L486-96
references.pmid: 15090367
references.citation: Antioxid Redox Signal. 2011 Sep 15;15(6):1517-30
references.pmid: 21194353
references.citation: Am J Physiol Heart Circ Physiol. 2003 Sep;285(3):H1113-22
references.pmid: 12763750
references.citation: Am J Respir Cell Mol Biol. 2007 Mar;36(3):304-12
references.pmid: 17008637
references.citation: J Clin Invest. 1991 Aug;88(2):674-9
references.pmid: 1864976
references.citation: Lab Invest. 1994 Apr;70(4):579-87
references.pmid: 8176898
references.citation: J Clin Invest. 1995 Mar;95(3):1363-9
references.pmid: 7883983
references.citation: Cell Physiol Biochem. 2010;25(1):113-22
references.pmid: 20054150
references.citation: Antioxid Redox Signal. 2006 Sep-Oct;8(9-10):1609-19
references.pmid: 16987015
references.citation: Nat Biotechnol. 2004 Aug;22(8):985-92
references.pmid: 15258593
references.citation: Oncogene. 2003 Sep 1;22(37):5734-54
references.pmid: 12947383
references.citation: Nat Rev Immunol. 2004 Mar;4(3):181-9
references.pmid: 15039755
references.citation: Cell Biochem Biophys. 2008;52(3):125-38
references.pmid: 18982455
references.citation: FASEB J. 1996 May;10(7):709-20
references.pmid: 8635688
references.citation: Am J Physiol Heart Circ Physiol. 2001 Nov;281(5):H2226-32
references.pmid: 11668087
references.citation: Nature. 2005 Sep 15;437(7057):426-31
references.pmid: 16163360
references.citation: Curr Vasc Pharmacol. 2006 Jan;4(1):67-78
references.pmid: 16472178
references.citation: J Clin Invest. 1973 Mar;52(3):741-4
references.pmid: 4346473
references.citation: Antioxid Redox Signal. 2009 Jun;11(6):1349-56
references.pmid: 19061438
references.citation: Microcirculation. 2006 Dec;13(8):633-44
references.pmid: 17085424
references.citation: Microcirculation. 2004 Sep;11(6):517-26
references.pmid: 15371132