Skip to main content

Advertisement

SpringerLink
Log in

ROS signaling and redox biology in endothelial cells

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

The purpose of this review is to provide an overview of redox mechanisms, sources and antioxidants that control signaling events in ECs. In particular, we describe which molecules are involved in redox signaling and how they influence the relationship between ECs and other vascular component with regard to angiogenesis. Recent and new tools to investigate physiological ROS signaling will be also discussed. Such findings are providing an overview of the ROS biology relevant for endothelial cells in the context of normal and pathological angiogenic conditions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Murphy MP, Holmgren A, Larsson NG, Halliwell B, Chang CJ, Kalyanaraman B, Rhee SG, Thornalley PJ, Partridge L, Gems D, Nystrom T, Belousov V, Schumacker PT, Winterbourn CC (2011) Unraveling the biological roles of reactive oxygen species. Cell Metab 13(4):361–366. doi:10.1016/j.cmet.2011.03.010

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Schieber M, Chandel NS (2014) ROS function in redox signaling and oxidative stress. Curr Biol CB 24(10):R453–R462. doi:10.1016/j.cub.2014.03.034

    CAS  PubMed  Google Scholar 

  3. Finkel T (2011) Signal transduction by reactive oxygen species. J Cell Biol 194(1):7–15. doi:10.1083/jcb.201102095

    CAS  PubMed Central  PubMed  Google Scholar 

  4. De Bock K, Georgiadou M, Schoors S, Kuchnio A, Wong BW, Cantelmo AR, Quaegebeur A, Ghesquiere B, Cauwenberghs S, Eelen G, Phng LK, Betz I, Tembuyser B, Brepoels K, Welti J, Geudens I, Segura I, Cruys B, Bifari F, Decimo I, Blanco R, Wyns S, Vangindertael J, Rocha S, Collins RT, Munck S, Daelemans D, Imamura H, Devlieger R, Rider M, Van Veldhoven PP, Schuit F, Bartrons R, Hofkens J, Fraisl P, Telang S, Deberardinis RJ, Schoonjans L, Vinckier S, Chesney J, Gerhardt H, Dewerchin M, Carmeliet P (2013) Role of PFKFB3-driven glycolysis in vessel sprouting. Cell 154(3):651–663. doi:10.1016/j.cell.2013.06.037

    PubMed  Google Scholar 

  5. Dickinson BC, Tang Y, Chang Z, Chang CJ (2011) A nuclear-localized fluorescent hydrogen peroxide probe for monitoring sirtuin-mediated oxidative stress responses in vivo. Chem Biol 18(8):943–948. doi:10.1016/j.chembiol.2011.07.005

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Bae YS, Oh H, Rhee SG, Yoo YD (2011) Regulation of reactive oxygen species generation in cell signaling. Mol Cells 32(6):491–509. doi:10.1007/s10059-011-0276-3

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Veal E, Day A (2011) Hydrogen peroxide as a signaling molecule. Antioxid Redox Signal 15(1):147–151. doi:10.1089/ars.2011.3968

    CAS  PubMed  Google Scholar 

  8. Breton-Romero R, Gonzalez de Orduna C, Romero N, Sanchez-Gomez FJ, de Alvaro C, Porras A, Rodriguez-Pascual F, Laranjinha J, Radi R, Lamas S (2012) Critical role of hydrogen peroxide signaling in the sequential activation of p38 MAPK and eNOS in laminar shear stress. Free Radic Biol Med 52(6):1093–1100. doi:10.1016/j.freeradbiomed.2011.12.026

    CAS  PubMed  Google Scholar 

  9. Evangelista AM, Thompson MD, Weisbrod RM, Pimental DR, Tong X, Bolotina VM, Cohen RA (2012) Redox regulation of SERCA2 is required for vascular endothelial growth factor-induced signaling and endothelial cell migration. Antioxid Redox Signal 17(8):1099–1108. doi:10.1089/ars.2011.4022

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Fernandes R, Hosoya K, Pereira P (2011) Reactive oxygen species downregulate glucose transport system in retinal endothelial cells. Am J Physiol Cell Physiol 300(4):C927–C936. doi:10.1152/ajpcell.00140.2010

    CAS  PubMed  Google Scholar 

  11. Kalwa H, Sartoretto JL, Martinelli R, Romero N, Steinhorn BS, Tao M, Ozaki CK, Carman CV, Michel T (2014) Central role for hydrogen peroxide in P2Y1 ADP receptor-mediated cellular responses in vascular endothelium. Proc Natl Acad Sci USA 111(9):3383–3388. doi:10.1073/pnas.1320854111

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Knock GA, Ward JP (2011) Redox regulation of protein kinases as a modulator of vascular function. Antioxid Redox Signal 15(6):1531–1547. doi:10.1089/ars.2010.3614

    CAS  PubMed  Google Scholar 

  13. Grant CM (2011) Regulation of translation by hydrogen peroxide. Antioxid Redox Signal 15(1):191–203. doi:10.1089/ars.2010.3699

    CAS  PubMed  Google Scholar 

  14. Ostman A, Frijhoff J, Sandin A, Bohmer FD (2011) Regulation of protein tyrosine phosphatases by reversible oxidation. J Biochem 150(4):345–356. doi:10.1093/jb/mvr104

    PubMed  Google Scholar 

  15. Roos G, Messens J (2011) Protein sulfenic acid formation: from cellular damage to redox regulation. Free Radic Biol Med 51(2):314–326. doi:10.1016/j.freeradbiomed.2011.04.031

    CAS  PubMed  Google Scholar 

  16. Roos G, Foloppe N, Messens J (2013) Understanding the pK(a) of redox cysteines: the key role of hydrogen bonding. Antioxid Redox Signal 18(1):94–127. doi:10.1089/ars.2012.4521

    CAS  PubMed  Google Scholar 

  17. Paulsen CE, Carroll KS (2013) Cysteine-mediated redox signaling: chemistry, biology, and tools for discovery. Chem Rev 113(7):4633–4679. doi:10.1021/cr300163e

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Forman HJ, Ursini F, Maiorino M (2014) An overview of mechanisms of redox signaling. J Mol Cell Cardiol 73:2–9. doi:10.1016/j.yjmcc.2014.01.018

    CAS  PubMed  Google Scholar 

  19. Steinberg SF (2013) Oxidative stress and sarcomeric proteins. Circ Res 112(2):393–405. doi:10.1161/CIRCRESAHA.111.300496

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Kaplan N, Urao N, Furuta E, Kim SJ, Razvi M, Nakamura Y, McKinney RD, Poole LB, Fukai T, Ushio-Fukai M (2011) Localized cysteine sulfenic acid formation by vascular endothelial growth factor: role in endothelial cell migration and angiogenesis. Free Radical Res 45(10):1124–1135. doi:10.3109/10715762.2011.602073

    CAS  Google Scholar 

  21. Jones DP, Go YM (2010) Redox compartmentalization and cellular stress. Diabetes Obes Metab 12(Suppl 2):116–125. doi:10.1111/j.1463-1326.2010.01266.x

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Kojer K, Bien M, Gangel H, Morgan B, Dick TP, Riemer J (2012) Glutathione redox potential in the mitochondrial intermembrane space is linked to the cytosol and impacts the Mia40 redox state. EMBO J 31(14):3169–3182. doi:10.1038/emboj.2012.165

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Go YM, Jones DP (2013) Thiol/disulfide redox states in signaling and sensing. Crit Rev Biochem Mol Biol 48(2):173–181. doi:10.3109/10409238.2013.764840

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Murphy MP (2012) Mitochondrial thiols in antioxidant protection and redox signaling: distinct roles for glutathionylation and other thiol modifications. Antioxid Redox Signal 16(6):476–495. doi:10.1089/ars.2011.4289

    CAS  PubMed  Google Scholar 

  25. Kaludercic N, Deshwal S, Di Lisa F (2014) Reactive oxygen species and redox compartmentalization. Front Physiol 5:285. doi:10.3389/fphys.2014.00285

    PubMed Central  PubMed  Google Scholar 

  26. Meyer AJ, Dick TP (2010) Fluorescent protein-based redox probes. Antioxid Redox Signal 13(5):621–650. doi:10.1089/ars.2009.2948

    CAS  PubMed  Google Scholar 

  27. Rhee SG, Chang TS, Jeong W, Kang D (2010) Methods for detection and measurement of hydrogen peroxide inside and outside of cells. Mol Cells 29(6):539–549. doi:10.1007/s10059-010-0082-3

    CAS  PubMed  Google Scholar 

  28. Kalyanaraman B, Darley-Usmar V, Davies KJ, Dennery PA, Forman HJ, Grisham MB, Mann GE, Moore K, Roberts LJ 2nd, Ischiropoulos H (2012) Measuring reactive oxygen and nitrogen species with fluorescent probes: challenges and limitations. Free Radic Biol Med 52(1):1–6. doi:10.1016/j.freeradbiomed.2011.09.030

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Karlsson M, Kurz T, Brunk UT, Nilsson SE, Frennesson CI (2010) What does the commonly used DCF test for oxidative stress really show? Biochem J 428(2):183–190. doi:10.1042/BJ20100208

    CAS  PubMed  Google Scholar 

  30. Burkitt MJ, Wardman P (2001) Cytochrome C is a potent catalyst of dichlorofluorescin oxidation: implications for the role of reactive oxygen species in apoptosis. Biochem Biophys Res Commun 282(1):329–333. doi:10.1006/bbrc.2001.4578

    CAS  PubMed  Google Scholar 

  31. Winterbourn CC (2014) The challenges of using fluorescent probes to detect and quantify specific reactive oxygen species in living cells. Biochim Biophys Acta 1840(2):730–738. doi:10.1016/j.bbagen.2013.05.004

    CAS  PubMed  Google Scholar 

  32. Lin VS, Dickinson BC, Chang CJ (2013) Boronate-based fluorescent probes: imaging hydrogen peroxide in living systems. Methods Enzymol 526:19–43. doi:10.1016/B978-0-12-405883-5.00002-8

    CAS  PubMed Central  PubMed  Google Scholar 

  33. Dickinson BC, Lin VS, Chang CJ (2013) Preparation and use of MitoPY1 for imaging hydrogen peroxide in mitochondria of live cells. Nat Protoc 8(6):1249–1259. doi:10.1038/nprot.2013.064

    PubMed Central  PubMed  Google Scholar 

  34. Cocheme HM, Quin C, McQuaker SJ, Cabreiro F, Logan A, Prime TA, Abakumova I, Patel JV, Fearnley IM, James AM, Porteous CM, Smith RA, Saeed S, Carre JE, Singer M, Gems D, Hartley RC, Partridge L, Murphy MP (2011) Measurement of H2O2 within living Drosophila during aging using a ratiometric mass spectrometry probe targeted to the mitochondrial matrix. Cell Metab 13(3):340–350. doi:10.1016/j.cmet.2011.02.003

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Cocheme HM, Logan A, Prime TA, Abakumova I, Quin C, McQuaker SJ, Patel JV, Fearnley IM, James AM, Porteous CM, Smith RA, Hartley RC, Partridge L, Murphy MP (2012) Using the mitochondria-targeted ratiometric mass spectrometry probe MitoB to measure H2O2 in living Drosophila. Nat Protoc 7(5):946–958. doi:10.1038/nprot.2012.035

    CAS  PubMed  Google Scholar 

  36. Ostergaard H, Henriksen A, Hansen FG, Winther JR (2001) Shedding light on disulfide bond formation: engineering a redox switch in green fluorescent protein. EMBO J 20(21):5853–5862. doi:10.1093/emboj/20.21.5853

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Dooley CT, Dore TM, Hanson GT, Jackson WC, Remington SJ, Tsien RY (2004) Imaging dynamic redox changes in mammalian cells with green fluorescent protein indicators. J Biol Chem 279(21):22284–22293. doi:10.1074/jbc.M312847200

    CAS  PubMed  Google Scholar 

  38. Bjornberg O, Ostergaard H, Winther JR (2006) Mechanistic insight provided by glutaredoxin within a fusion to redox-sensitive yellow fluorescent protein. Biochemistry 45(7):2362–2371. doi:10.1021/bi0522495

    PubMed  Google Scholar 

  39. Morgan B, Sobotta MC, Dick TP (2011) Measuring E(GSH) and H2O2 with roGFP2-based redox probes. Free Radic Biol Med 51(11):1943–1951. doi:10.1016/j.freeradbiomed.2011.08.035

    CAS  PubMed  Google Scholar 

  40. Gutscher M, Pauleau AL, Marty L, Brach T, Wabnitz GH, Samstag Y, Meyer AJ, Dick TP (2008) Real-time imaging of the intracellular glutathione redox potential. Nat Methods 5(6):553–559. doi:10.1038/nmeth.1212

    CAS  PubMed  Google Scholar 

  41. Gutscher M, Sobotta MC, Wabnitz GH, Ballikaya S, Meyer AJ, Samstag Y, Dick TP (2009) Proximity-based protein thiol oxidation by H2O2-scavenging peroxidases. J Biol Chem 284(46):31532–31540. doi:10.1074/jbc.M109.059246

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Morgan B, Ezerina D, Amoako TN, Riemer J, Seedorf M, Dick TP (2013) Multiple glutathione disulfide removal pathways mediate cytosolic redox homeostasis. Nat Chem Biol 9(2):119–125. doi:10.1038/nchembio.1142

    CAS  PubMed  Google Scholar 

  43. Bhaskar A, Munshi M, Khan SZ, Fatima S, Arya R, Jameel S, Singh A (2015) Measuring glutathione redox potential of HIV-1-infected macrophages. J Biol Chem 290(2):1020–1038. doi:10.1074/jbc.M114.588913

    CAS  PubMed Central  PubMed  Google Scholar 

  44. Albrecht SC, Sobotta MC, Bausewein D, Aller I, Hell R, Dick TP, Meyer AJ (2014) Redesign of genetically encoded biosensors for monitoring mitochondrial redox status in a broad range of model eukaryotes. J Biomol Screen 19(3):379–386. doi:10.1177/1087057113499634

    CAS  PubMed  Google Scholar 

  45. Back P, De Vos WH, Depuydt GG, Matthijssens F, Vanfleteren JR, Braeckman BP (2012) Exploring real-time in vivo redox biology of developing and aging Caenorhabditis elegans. Free Radic Biol Med 52(5):850–859. doi:10.1016/j.freeradbiomed.2011.11.037

    CAS  PubMed  Google Scholar 

  46. Barata AG, Dick TP (2013) In vivo imaging of H2O2 production in Drosophila. Methods Enzymol 526:61–82. doi:10.1016/B978-0-12-405883-5.00004-1

    CAS  PubMed  Google Scholar 

  47. Breckwoldt MO, Pfister FM, Bradley PM, Marinkovic P, Williams PR, Brill MS, Plomer B, Schmalz A, St Clair DK, Naumann R, Griesbeck O, Schwarzlander M, Godinho L, Bareyre FM, Dick TP, Kerschensteiner M, Misgeld T (2014) Multiparametric optical analysis of mitochondrial redox signals during neuronal physiology and pathology in vivo. Nat Med 20(5):555–560. doi:10.1038/nm.3520

    CAS  PubMed  Google Scholar 

  48. Belousov VV, Fradkov AF, Lukyanov KA, Staroverov DB, Shakhbazov KS, Terskikh AV, Lukyanov S (2006) Genetically encoded fluorescent indicator for intracellular hydrogen peroxide. Nat Methods 3(4):281–286. doi:10.1038/nmeth866

    CAS  PubMed  Google Scholar 

  49. Malinouski M, Zhou Y, Belousov VV, Hatfield DL, Gladyshev VN (2011) Hydrogen peroxide probes directed to different cellular compartments. PLoS One 6(1):e14564. doi:10.1371/journal.pone.0014564

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Mishina NM, Tyurin-Kuzmin PA, Markvicheva KN, Vorotnikov AV, Tkachuk VA, Laketa V, Schultz C, Lukyanov S, Belousov VV (2011) Does cellular hydrogen peroxide diffuse or act locally? Antioxid Redox Signal 14(1):1–7. doi:10.1089/ars.2010.3539

    CAS  PubMed  Google Scholar 

  51. Markvicheva KN, Bilan DS, Mishina NM, Gorokhovatsky AY, Vinokurov LM, Lukyanov S, Belousov VV (2011) A genetically encoded sensor for H2O2 with expanded dynamic range. Bioorg Med Chem 19(3):1079–1084. doi:10.1016/j.bmc.2010.07.014

    CAS  PubMed  Google Scholar 

  52. Bilan DS, Pase L, Joosen L, Gorokhovatsky AY, Ermakova YG, Gadella TW, Grabher C, Schultz C, Lukyanov S, Belousov VV (2013) HyPer-3: a genetically encoded H(2)O(2) probe with improved performance for ratiometric and fluorescence lifetime imaging. ACS Chem Biol 8(3):535–542. doi:10.1021/cb300625g

    CAS  PubMed  Google Scholar 

  53. Sartoretto JL, Kalwa H, Romero N, Michel T (2013) In vivo imaging of nitric oxide and hydrogen peroxide in cardiac myocytes. Methods Enzymol 528:61–78. doi:10.1016/B978-0-12-405881-1.00004-5

    CAS  PubMed  Google Scholar 

  54. Mishina NM, Markvicheva KN, Bilan DS, Matlashov ME, Shirmanova MV, Liebl D, Schultz C, Lukyanov S, Belousov VV (2013) Visualization of intracellular hydrogen peroxide with HyPer, a genetically encoded fluorescent probe. Methods Enzymol 526:45–59. doi:10.1016/B978-0-12-405883-5.00003-X

    CAS  PubMed  Google Scholar 

  55. Roma LP, Duprez J, Takahashi HK, Gilon P, Wiederkehr A, Jonas JC (2012) Dynamic measurements of mitochondrial hydrogen peroxide concentration and glutathione redox state in rat pancreatic beta-cells using ratiometric fluorescent proteins: confounding effects of pH with HyPer but not roGFP1. Biochem J 441(3):971–978. doi:10.1042/BJ20111770

    CAS  PubMed  Google Scholar 

  56. Wang W, Fang H, Groom L, Cheng A, Zhang W, Liu J, Wang X, Li K, Han P, Zheng M, Yin J, Mattson MP, Kao JP, Lakatta EG, Sheu SS, Ouyang K, Chen J, Dirksen RT, Cheng H (2008) Superoxide flashes in single mitochondria. Cell 134(2):279–290. doi:10.1016/j.cell.2008.06.017

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Schwarzlander M, Logan DC, Fricker MD, Sweetlove LJ (2011) The circularly permuted yellow fluorescent protein cpYFP that has been used as a superoxide probe is highly responsive to pH but not superoxide in mitochondria: implications for the existence of superoxide ‘flashes’. Biochem J 437(3):381–387. doi:10.1042/BJ20110883

    PubMed  Google Scholar 

  58. Schwarzlander M, Wagner S, Ermakova YG, Belousov VV, Radi R, Beckman JS, Buettner GR, Demaurex N, Duchen MR, Forman HJ, Fricker MD, Gems D, Halestrap AP, Halliwell B, Jakob U, Johnston IG, Jones NS, Logan DC, Morgan B, Muller FL, Nicholls DG, Remington SJ, Schumacker PT, Winterbourn CC, Sweetlove LJ, Meyer AJ, Dick TP, Murphy MP (2014) The ‘mitoflash’ probe cpYFP does not respond to superoxide. Nature 514(7523):E12–E14. doi:10.1038/nature13858

    PubMed  Google Scholar 

  59. Zhao BS, Zhang G, Zeng S, He C, Chen PR (2013) Probing subcellular organic hydroperoxide formation via a genetically encoded ratiometric and reversible fluorescent indicator. Integr Biol: Quant Biosci Nano Macro 5(12):1485–1489. doi:10.1039/c3ib40209f

    CAS  Google Scholar 

  60. Zhao BS, Liang Y, Song Y, Zheng C, Hao Z, Chen PR (2010) A highly selective fluorescent probe for visualization of organic hydroperoxides in living cells. J Am Chem Soc 132(48):17065–17067. doi:10.1021/ja1071114

    CAS  PubMed  Google Scholar 

  61. Kolossov VL, Leslie MT, Chatterjee A, Sheehan BM, Kenis PJ, Gaskins HR (2012) Forster resonance energy transfer-based sensor targeting endoplasmic reticulum reveals highly oxidative environment. Exp Biol Med (Maywood) 237(6):652–662. doi:10.1258/ebm.2012.011436

    CAS  Google Scholar 

  62. Abraham BG, Santala V, Tkachenko NV, Karp M (2014) Fluorescent protein-based FRET sensor for intracellular monitoring of redox status in bacteria at single cell level. Anal Bioanal Chem 406(28):7195–7204. doi:10.1007/s00216-014-8165-1

    CAS  PubMed  Google Scholar 

  63. Enyedi B, Zana M, Donko A, Geiszt M (2013) Spatial and temporal analysis of NADPH oxidase-generated hydrogen peroxide signals by novel fluorescent reporter proteins. Antioxid Redox Signal 19(6):523–534. doi:10.1089/ars.2012.4594

    CAS  PubMed  Google Scholar 

  64. De Bock K, Georgiadou M, Carmeliet P (2013) Role of endothelial cell metabolism in vessel sprouting. Cell Metab 18(5):634–647. doi:10.1016/j.cmet.2013.08.001

    PubMed  Google Scholar 

  65. Kim YW, Byzova TV (2014) Oxidative stress in angiogenesis and vascular disease. Blood 123(5):625–631. doi:10.1182/blood-2013-09-512749

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Li H, Horke S, Forstermann U (2014) Vascular oxidative stress, nitric oxide and atherosclerosis. Atherosclerosis 237(1):208–219. doi:10.1016/j.atherosclerosis.2014.09.001

    CAS  PubMed  Google Scholar 

  67. Su Q, Qin DN, Wang FX, Ren J, Li HB, Zhang M, Yang Q, Miao YW, Yu XJ, Qi J, Zhu Z, Zhu GQ, Kang YM (2014) Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin-angiotensin system and proinflammatory cytokines in hypertension. Toxicol Appl Pharmacol 276(2):115–120. doi:10.1016/j.taap.2014.02.002

    CAS  PubMed  Google Scholar 

  68. Zuo L, Rose BA, Roberts WJ, He F, Banes-Berceli AK (2014) Molecular characterization of reactive oxygen species in systemic and pulmonary hypertension. Am J Hypertens 27(5):643–650. doi:10.1093/ajh/hpt292

    CAS  PubMed  Google Scholar 

  69. Kaneto H, Katakami N, Matsuhisa M, Matsuoka TA (2010) Role of reactive oxygen species in the progression of type 2 diabetes and atherosclerosis. Mediators Inflamm 2010:453892. doi:10.1155/2010/453892

    PubMed Central  PubMed  Google Scholar 

  70. Ray PD, Huang BW, Tsuji Y (2012) Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal 24(5):981–990. doi:10.1016/j.cellsig.2012.01.008

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Bir SC, Kolluru GK, Fang K, Kevil CG (2012) Redox balance dynamically regulates vascular growth and remodeling. Semin Cell Dev Biol 23(7):745–757. doi:10.1016/j.semcdb.2012.05.003

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Takac I, Schroder K, Brandes RP (2012) The Nox family of NADPH oxidases: friend or foe of the vascular system? Curr Hypertens Rep 14(1):70–78. doi:10.1007/s11906-011-0238-3

    CAS  PubMed  Google Scholar 

  73. Manea A (2010) NADPH oxidase-derived reactive oxygen species: involvement in vascular physiology and pathology. Cell Tissue Res 342(3):325–339. doi:10.1007/s00441-010-1060-y

    CAS  PubMed  Google Scholar 

  74. Takac I, Schroder K, Zhang L, Lardy B, Anilkumar N, Lambeth JD, Shah AM, Morel F, Brandes RP (2011) The E-loop is involved in hydrogen peroxide formation by the NADPH oxidase Nox4. J Biol Chem 286(15):13304–13313. doi:10.1074/jbc.M110.192138

    CAS  PubMed Central  PubMed  Google Scholar 

  75. De Deken X, Corvilain B, Dumont JE, Miot F (2014) Roles of DUOX-mediated hydrogen peroxide in metabolism, host defense, and signaling. Antioxid Redox Signal 20(17):2776–2793. doi:10.1089/ars.2013.5602

    PubMed  Google Scholar 

  76. Konior A, Schramm A, Czesnikiewicz-Guzik M, Guzik TJ (2014) NADPH oxidases in vascular pathology. Antioxid Redox Signal 20(17):2794–2814. doi:10.1089/ars.2013.5607

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Lassegue B, Griendling KK (2010) NADPH oxidases: functions and pathologies in the vasculature. Arterioscler Thromb Vasc Biol 30(4):653–661. doi:10.1161/ATVBAHA.108.181610

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Anilkumar N, San Jose G, Sawyer I, Santos CX, Sand C, Brewer AC, Warren D, Shah AM (2013) A 28-kDa splice variant of NADPH oxidase-4 is nuclear-localized and involved in redox signaling in vascular cells. Arterioscler Thromb Vasc Biol 33(4):e104–e112. doi:10.1161/ATVBAHA.112.300956

    CAS  PubMed  Google Scholar 

  79. Schroder K, Zhang M, Benkhoff S, Mieth A, Pliquett R, Kosowski J, Kruse C, Luedike P, Michaelis UR, Weissmann N, Dimmeler S, Shah AM, Brandes RP (2012) Nox4 is a protective reactive oxygen species generating vascular NADPH oxidase. Circ Res 110(9):1217–1225. doi:10.1161/CIRCRESAHA.112.267054

    PubMed  Google Scholar 

  80. Chen K, Kirber MT, Xiao H, Yang Y, Keaney JF Jr (2008) Regulation of ROS signal transduction by NADPH oxidase 4 localization. J Cell Biol 181(7):1129–1139. doi:10.1083/jcb.200709049

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Diebold I, Flugel D, Becht S, Belaiba RS, Bonello S, Hess J, Kietzmann T, Gorlach A (2010) The hypoxia-inducible factor-2alpha is stabilized by oxidative stress involving NOX4. Antioxid Redox Signal 13(4):425–436. doi:10.1089/ars.2009.3014

    CAS  PubMed  Google Scholar 

  82. Craige SM, Chen K, Pei Y, Li C, Huang X, Chen C, Shibata R, Sato K, Walsh K, Keaney JF Jr (2011) NADPH oxidase 4 promotes endothelial angiogenesis through endothelial nitric oxide synthase activation. Circulation 124(6):731–740. doi:10.1161/CIRCULATIONAHA.111.030775

    CAS  PubMed Central  PubMed  Google Scholar 

  83. Tung JJ, Kitajewski J (2010) Chloride intracellular channel 1 functions in endothelial cell growth and migration. J Angiogenesis Res 2:23. doi:10.1186/2040-2384-2-23

    Google Scholar 

  84. Gray SP, Di Marco E, Okabe J, Szyndralewiez C, Heitz F, Montezano AC, de Haan JB, Koulis C, El-Osta A, Andrews KL, Chin-Dusting JP, Touyz RM, Wingler K, Cooper ME, Schmidt HH, Jandeleit-Dahm KA (2013) NADPH oxidase 1 plays a key role in diabetes mellitus-accelerated atherosclerosis. Circulation 127(18):1888–1902. doi:10.1161/CIRCULATIONAHA.112.132159

    CAS  PubMed  Google Scholar 

  85. Lee JH, Joo JH, Kim J, Lim HJ, Kim S, Curtiss L, Seong JK, Cui W, Yabe-Nishimura C, Bae YS (2013) Interaction of NADPH oxidase 1 with Toll-like receptor 2 induces migration of smooth muscle cells. Cardiovasc Res 99(3):483–493. doi:10.1093/cvr/cvt107

    CAS  PubMed  Google Scholar 

  86. Paletta-Silva R, Rocco-Machado N, Meyer-Fernandes JR (2013) NADPH oxidase biology and the regulation of tyrosine kinase receptor signaling and cancer drug cytotoxicity. Int J Mol Sci 14(2):3683–3704. doi:10.3390/ijms14023683

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Pi X, Xie L, Portbury AL, Kumar S, Lockyer P, Li X, Patterson C (2014) NADPH oxidase-generated reactive oxygen species are required for stromal cell-derived factor-1alpha-stimulated angiogenesis. Arterioscler Thromb Vasc Biol 34(9):2023–2032. doi:10.1161/ATVBAHA.114.303733

    CAS  PubMed  Google Scholar 

  88. Jiang F, Zhang Y, Dusting GJ (2011) NADPH oxidase-mediated redox signaling: roles in cellular stress response, stress tolerance, and tissue repair. Pharmacol Rev 63(1):218–242. doi:10.1124/pr.110.002980

    CAS  PubMed  Google Scholar 

  89. Lassegue B, San Martin A, Griendling KK (2012) Biochemistry, physiology, and pathophysiology of NADPH oxidases in the cardiovascular system. Circ Res 110(10):1364–1390. doi:10.1161/CIRCRESAHA.111.243972

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Gregg JL, Turner RM 2nd, Chang G, Joshi D, Zhan Y, Chen L, Maranchie JK (2014) NADPH oxidase NOX4 supports renal tumorigenesis by promoting the expression and nuclear accumulation of HIF2alpha. Cancer Res 74(13):3501–3511. doi:10.1158/0008-5472.CAN-13-2979

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Wang H, Yang Z, Jiang Y, Hartnett ME (2014) Endothelial NADPH oxidase 4 mediates vascular endothelial growth factor receptor 2-induced intravitreal neovascularization in a rat model of retinopathy of prematurity. Mol Vis 20:231–241

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Ray R, Murdoch CE, Wang M, Santos CX, Zhang M, Alom-Ruiz S, Anilkumar N, Ouattara A, Cave AC, Walker SJ, Grieve DJ, Charles RL, Eaton P, Brewer AC, Shah AM (2011) Endothelial Nox4 NADPH oxidase enhances vasodilatation and reduces blood pressure in vivo. Arterioscler Thromb Vasc Biol 31(6):1368–1376. doi:10.1161/ATVBAHA.110.219238

    CAS  PubMed  Google Scholar 

  93. Meng D, Mei A, Liu J, Kang X, Shi X, Qian R, Chen S (2012) NADPH oxidase 4 mediates insulin-stimulated HIF-1alpha and VEGF expression, and angiogenesis in vitro. PLoS One 7(10):e48393. doi:10.1371/journal.pone.0048393

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Johnson BD, Mather KJ, Wallace JP (2011) Mechanotransduction of shear in the endothelium: basic studies and clinical implications. Vasc Med 16(5):365–377. doi:10.1177/1358863X11422109

    PubMed  Google Scholar 

  95. Chiu JJ, Chien S (2011) Effects of disturbed flow on vascular endothelium: pathophysiological basis and clinical perspectives. Physiol Rev 91(1):327–387. doi:10.1152/physrev.00047.2009

    PubMed  Google Scholar 

  96. White SJ, Hayes EM, Lehoux S, Jeremy JY, Horrevoets AJ, Newby AC (2011) Characterization of the differential response of endothelial cells exposed to normal and elevated laminar shear stress. J Cell Physiol 226(11):2841–2848. doi:10.1002/jcp.22629

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Lu X, Guo X, Wassall CD, Kemple MD, Unthank JL, Kassab GS (2011) Reactive oxygen species cause endothelial dysfunction in chronic flow overload. J Appl Physiol (1985) 110(2):520–527. doi:10.1152/japplphysiol.00786.2009

    CAS  Google Scholar 

  98. Montezano AC, Touyz RM (2012) Oxidative stress, Noxs, and hypertension: experimental evidence and clinical controversies. Ann Med 44(Suppl 1):S2–16. doi:10.3109/07853890.2011.653393

    CAS  PubMed  Google Scholar 

  99. Chouchani ET, Pell VR, Gaude E, Aksentijevic D, Sundier SY, Robb EL, Logan A, Nadtochiy SM, Ord EN, Smith AC, Eyassu F, Shirley R, Hu CH, Dare AJ, James AM, Rogatti S, Hartley RC, Eaton S, Costa AS, Brookes PS, Davidson SM, Duchen MR, Saeb-Parsy K, Shattock MJ, Robinson AJ, Work LM, Frezza C, Krieg T, Murphy MP (2014) Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 515(7527):431–435. doi:10.1038/nature13909

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Finkel T (2012) Signal transduction by mitochondrial oxidants. J Biol Chem 287(7):4434–4440. doi:10.1074/jbc.R111.271999

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Breton-Romero R, Acin-Perez R, Rodriguez-Pascual F, Martinez-Molledo M, Brandes RP, Rial E, Enriquez JA, Lamas S (2014) Laminar shear stress regulates mitochondrial dynamics, bioenergetics responses and PRX3 activation in endothelial cells. Biochim Biophys Acta 1843(11):2403–2413. doi:10.1016/j.bbamcr.2014.07.003

    CAS  PubMed  Google Scholar 

  102. Hernansanz-Agustin P, Izquierdo-Alvarez A, Sanchez-Gomez FJ, Ramos E, Villa-Pina T, Lamas S, Bogdanova A, Martinez-Ruiz A (2014) Acute hypoxia produces a superoxide burst in cells. Free Radic Biol Med 71:146–156. doi:10.1016/j.freeradbiomed.2014.03.011

    CAS  PubMed  Google Scholar 

  103. Katakam PV, Wappler EA, Katz PS, Rutkai I, Institoris A, Domoki F, Gaspar T, Grovenburg SM, Snipes JA, Busija DW (2013) Depolarization of mitochondria in endothelial cells promotes cerebral artery vasodilation by activation of nitric oxide synthase. Arterioscler Thromb Vasc Biol 33(4):752–759. doi:10.1161/ATVBAHA.112.300560

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Kotiadis VN, Duchen MR, Osellame LD (2014) Mitochondrial quality control and communications with the nucleus are important in maintaining mitochondrial function and cell health. Biochim Biophys Acta 1840(4):1254–1265. doi:10.1016/j.bbagen.2013.10.041

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Al-Mehdi AB, Pastukh VM, Swiger BM, Reed DJ, Patel MR, Bardwell GC, Pastukh VV, Alexeyev MF, Gillespie MN (2012) Perinuclear mitochondrial clustering creates an oxidant-rich nuclear domain required for hypoxia-induced transcription. Sci Signal 5 (231):ra47. doi:10.1126/scisignal.2002712

  106. Park J, Lee J, Choi C (2011) Mitochondrial network determines intracellular ROS dynamics and sensitivity to oxidative stress through switching inter-mitochondrial messengers. PLoS One 6(8):e23211. doi:10.1371/journal.pone.0023211

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Shah GN, Morofuji Y, Banks WA, Price TO (2013) High glucose-induced mitochondrial respiration and reactive oxygen species in mouse cerebral pericytes is reversed by pharmacological inhibition of mitochondrial carbonic anhydrases: implications for cerebral microvascular disease in diabetes. Biochem Biophys Res Commun 440(2):354–358. doi:10.1016/j.bbrc.2013.09.086

    CAS  PubMed  Google Scholar 

  108. Patel H, Chen J, Das KC, Kavdia M (2013) Hyperglycemia induces differential change in oxidative stress at gene expression and functional levels in HUVEC and HMVEC. Cardiovasc Diabetol 12:142. doi:10.1186/1475-2840-12-142

    PubMed Central  PubMed  Google Scholar 

  109. Dymkowska D, Drabarek B, Podszywalow-Bartnicka P, Szczepanowska J, Zablocki K (2014) Hyperglycaemia modifies energy metabolism and reactive oxygen species formation in endothelial cells in vitro. Arch Biochem Biophys 542:7–13. doi:10.1016/j.abb.2013.11.008

    CAS  PubMed  Google Scholar 

  110. Forstermann U, Sessa WC (2012) Nitric oxide synthases: regulation and function. Eur Heart J 33 (7):829–837, 837a–837d. doi:10.1093/eurheartj/ehr304

  111. Crabtree MJ, Hale AB, Channon KM (2011) Dihydrofolate reductase protects endothelial nitric oxide synthase from uncoupling in tetrahydrobiopterin deficiency. Free Radic Biol Med 50(11):1639–1646. doi:10.1016/j.freeradbiomed.2011.03.010

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Mugoni V, Postel R, Catanzaro V, De Luca E, Turco E, Digilio G, Silengo L, Murphy MP, Medana C, Stainier DY, Bakkers J, Santoro MM (2013) Ubiad1 is an antioxidant enzyme that regulates eNOS activity by CoQ10 synthesis. Cell 152(3):504–518. doi:10.1016/j.cell.2013.01.013

    CAS  PubMed Central  PubMed  Google Scholar 

  113. Tejero J, Stuehr D (2013) Tetrahydrobiopterin in nitric oxide synthase. IUBMB Life 65(4):358–365. doi:10.1002/iub.1136

    CAS  PubMed  Google Scholar 

  114. Heiss C, Rodriguez-Mateos A, Kelm M (2014) Central role of eNOS in the maintenance of endothelial homeostasis. Antioxid Redox Signal. doi:10.1089/ars.2014.6158

    PubMed  Google Scholar 

  115. Cassuto J, Dou H, Czikora I, Szabo A, Patel VS, Kamath V, Belin de Chantemele E, Feher A, Romero MJ, Bagi Z (2014) Peroxynitrite disrupts endothelial caveolae leading to eNOS uncoupling and diminished flow-mediated dilation in coronary arterioles of diabetic patients. Diabetes 63(4):1381–1393. doi:10.2337/db13-0577

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Priya MK, Sahu G, Soto-Pantoja DR, Goldy N, Sundaresan AM, Jadhav V, Barathkumar TR, Saran U, Jaffar Ali BM, Roberts DD, Bera AK, Chatterjee S (2014) Tipping off endothelial tubes: nitric oxide drives tip cells. Angiogenesis. doi:10.1007/s10456-014-9455-0

    PubMed  Google Scholar 

  117. Siddiqui MR, Komarova YA, Vogel SM, Gao X, Bonini MG, Rajasingh J, Zhao YY, Brovkovych V, Malik AB (2011) Caveolin-1-eNOS signaling promotes p190RhoGAP-A nitration and endothelial permeability. J Cell Biol 193(5):841–850. doi:10.1083/jcb.201012129

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Tian J, Hou Y, Lu Q, Wiseman DA, Vasconcelos Fonsesca F, Elms S, Fulton DJ, Black SM (2010) A novel role for caveolin-1 in regulating endothelial nitric oxide synthase activation in response to H2O2 and shear stress. Free Radic Biol Med 49(2):159–170. doi:10.1016/j.freeradbiomed.2010.03.023

    CAS  PubMed  Google Scholar 

  119. Schulman IH, Hare JM (2012) Regulation of cardiovascular cellular processes by S-nitrosylation. Biochim Biophys Acta 1820(6):752–762. doi:10.1016/j.bbagen.2011.04.002

    CAS  PubMed  Google Scholar 

  120. Duran WN, Beuve AV, Sanchez FA (2013) Nitric oxide, S-nitrosation, and endothelial permeability. IUBMB Life 65(10):819–826. doi:10.1002/iub.1204

    CAS  PubMed Central  PubMed  Google Scholar 

  121. Moraes MS, Costa PE, Batista WL, Paschoalin T, Curcio MF, Borges RE, Taha MO, Fonseca FV, Stern A, Monteiro HP (2014) Endothelium-derived nitric oxide (NO) activates the NO-epidermal growth factor receptor-mediated signaling pathway in bradykinin-stimulated angiogenesis. Arch Biochem Biophys 558:14–27. doi:10.1016/j.abb.2014.06.011

    CAS  PubMed  Google Scholar 

  122. Chen CA, Wang TY, Varadharaj S, Reyes LA, Hemann C, Talukder MA, Chen YR, Druhan LJ, Zweier JL (2010) S-glutathionylation uncouples eNOS and regulates its cellular and vascular function. Nature 468(7327):1115–1118. doi:10.1038/nature09599

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Sugiyama T, Michel T (2010) Thiol-metabolizing proteins and endothelial redox state: differential modulation of eNOS and biopterin pathways. Am J Physiol Heart Circ Physiol 298(1):H194–H201. doi:10.1152/ajpheart.00767.2009

    CAS  PubMed Central  PubMed  Google Scholar 

  124. Kelley EE, Khoo NK, Hundley NJ, Malik UZ, Freeman BA, Tarpey MM (2010) Hydrogen peroxide is the major oxidant product of xanthine oxidase. Free Radic Biol Med 48(4):493–498. doi:10.1016/j.freeradbiomed.2009.11.012

    CAS  PubMed Central  PubMed  Google Scholar 

  125. Battelli MG, Polito L, Bolognesi A (2014) Xanthine oxidoreductase in atherosclerosis pathogenesis: not only oxidative stress. Atherosclerosis 237(2):562–567. doi:10.1016/j.atherosclerosis.2014.10.006

    CAS  PubMed  Google Scholar 

  126. Battelli MG, Bolognesi A, Polito L (2014) Pathophysiology of circulating xanthine oxidoreductase: new emerging roles for a multi-tasking enzyme. Biochim Biophys Acta 1842(9):1502–1517. doi:10.1016/j.bbadis.2014.05.022

    CAS  PubMed  Google Scholar 

  127. Lee MC, Velayutham M, Komatsu T, Hille R, Zweier JL (2014) Measurement and characterization of superoxide generation from xanthine dehydrogenase: a redox-regulated pathway of radical generation in ischemic tissues. Biochemistry 53(41):6615–6623. doi:10.1021/bi500582r

    CAS  PubMed  Google Scholar 

  128. Wang G, Qian P, Jackson FR, Qian G, Wu G (2008) Sequential activation of JAKs, STATs and xanthine dehydrogenase/oxidase by hypoxia in lung microvascular endothelial cells. Int J Biochem Cell Biol 40(3):461–470. doi:10.1016/j.biocel.2007.08.008

    CAS  PubMed Central  PubMed  Google Scholar 

  129. Nanduri J, Vaddi DR, Khan SA, Wang N, Makerenko V, Prabhakar NR (2013) Xanthine oxidase mediates hypoxia-inducible factor-2alpha degradation by intermittent hypoxia. PLoS One 8(10):e75838. doi:10.1371/journal.pone.0075838

    CAS  PubMed Central  PubMed  Google Scholar 

  130. Tsirmoula S, Lamprou M, Hatziapostolou M, Kieffer N, Papadimitriou E (2015) Pleiotrophin-induced endothelial cell migration is regulated by xanthine oxidase-mediated generation of reactive oxygen species. Microvasc Res 98C:74–81. doi:10.1016/j.mvr.2015.01.001

    Google Scholar 

  131. Dunn LL, Buckle AM, Cooke JP, Ng MK (2010) The emerging role of the thioredoxin system in angiogenesis. Arterioscler Thromb Vasc Biol 30(11):2089–2098. doi:10.1161/ATVBAHA.110.209643

    CAS  PubMed Central  PubMed  Google Scholar 

  132. Go YM, Son DJ, Park H, Orr M, Hao L, Takabe W, Kumar S, Kang DW, Kim CW, Jo H, Jones DP (2014) Disturbed flow enhances inflammatory signaling and atherogenesis by increasing thioredoxin-1 level in endothelial cell nuclei. PLoS One 9(9):e108346. doi:10.1371/journal.pone.0108346

    PubMed Central  PubMed  Google Scholar 

  133. Goy C, Czypiorski P, Altschmied J, Jakob S, Rabanter LL, Brewer AC, Ale-Agha N, Dyballa-Rukes N, Shah AM, Haendeler J (2014) The imbalanced redox status in senescent endothelial cells is due to dysregulated Thioredoxin-1 and NADPH oxidase 4. Exp Gerontol 56:45–52. doi:10.1016/j.exger.2014.03.005

    CAS  PubMed  Google Scholar 

  134. Abdelsaid MA, Matragoon S, El-Remessy AB (2013) Thioredoxin-interacting protein expression is required for VEGF-mediated angiogenic signal in endothelial cells. Antioxid Redox Signal 19(18):2199–2212. doi:10.1089/ars.2012.4761

    CAS  PubMed Central  PubMed  Google Scholar 

  135. Spindel ON, Yan C, Berk BC (2012) Thioredoxin-interacting protein mediates nuclear-to-plasma membrane communication: role in vascular endothelial growth factor 2 signaling. Arterioscler Thromb Vasc Biol 32(5):1264–1270. doi:10.1161/ATVBAHA.111.244681

    CAS  PubMed  Google Scholar 

  136. World C, Spindel ON, Berk BC (2011) Thioredoxin-interacting protein mediates TRX1 translocation to the plasma membrane in response to tumor necrosis factor-alpha: a key mechanism for vascular endothelial growth factor receptor-2 transactivation by reactive oxygen species. Arterioscler Thromb Vasc Biol 31(8):1890–1897. doi:10.1161/ATVBAHA.111.226340

  137. Welsh SJ, Bellamy WT, Briehl MM, Powis G (2002) The redox protein thioredoxin-1 (Trx-1) increases hypoxia-inducible factor 1alpha protein expression: Trx-1 overexpression results in increased vascular endothelial growth factor production and enhanced tumor angiogenesis. Cancer Res 62(17):5089–5095

    CAS  PubMed  Google Scholar 

  138. Takagi Y, Kikuta K, Moriwaki T, Aoki T, Nozaki K, Hashimoto N, Miyamoto S (2011) Expression of thioredoxin-1 and hypoxia inducible factor-1alpha in cerebral arteriovenous malformations: possible role of redox regulatory factor in neoangiogenic property. Surg Neurol Int 2:61. doi:10.4103/2152-7806.80356

    PubMed Central  PubMed  Google Scholar 

  139. Samuel SM, Thirunavukkarasu M, Penumathsa SV, Koneru S, Zhan L, Maulik G, Sudhakaran PR, Maulik N (2010) Thioredoxin-1 gene therapy enhances angiogenic signaling and reduces ventricular remodeling in infarcted myocardium of diabetic rats. Circulation 121(10):1244–1255. doi:10.1161/CIRCULATIONAHA.109.872481

    CAS  PubMed Central  PubMed  Google Scholar 

  140. Dai S, He Y, Zhang H, Yu L, Wan T, Xu Z, Jones D, Chen H, Min W (2009) Endothelial-specific expression of mitochondrial thioredoxin promotes ischemia-mediated arteriogenesis and angiogenesis. Arterioscler Thromb Vasc Biol 29(4):495–502. doi:10.1161/ATVBAHA.108.180349

    CAS  PubMed Central  PubMed  Google Scholar 

  141. Sibbing D, Pfeufer A, Perisic T, Mannes AM, Fritz-Wolf K, Unwin S, Sinner MF, Gieger C, Gloeckner CJ, Wichmann HE, Kremmer E, Schafer Z, Walch A, Hinterseer M, Nabauer M, Kaab S, Kastrati A, Schomig A, Meitinger T, Bornkamm GW, Conrad M, von Beckerath N (2011) Mutations in the mitochondrial thioredoxin reductase gene TXNRD2 cause dilated cardiomyopathy. Eur Heart J 32(9):1121–1133. doi:10.1093/eurheartj/ehq507

    CAS  PubMed  Google Scholar 

  142. Beck H, Hellfritsch J, Kirsch J, Schneider M, Perisic T, Wortmann M, Frijhoff J, Dagnell M, Fey T, Esposito I, Kolle P, Pogoda K, Ingold I, Angeli JP, Kuhlencordt P, Ostman A, Pohl U, Conrad M (2015) Knockout of mitochondrial thioredoxin reductase stabilizes prolyl hydroxylase 2 and inhibits tumor growth and tumor-derived angiogenesis. Antioxid Redox Signal. doi:10.1089/ars.2014.5889

    PubMed Central  PubMed  Google Scholar 

  143. Chen B, Wang W, Shen T, Qi R (2013) Thioredoxin1 downregulates oxidized low-density lipoprotein-induced adhesion molecule expression via Smad3 protein. PLoS One 8(9):e76226. doi:10.1371/journal.pone.0076226

    CAS  PubMed Central  PubMed  Google Scholar 

  144. Rhee SG, Woo HA (2011) Multiple functions of peroxiredoxins: peroxidases, sensors and regulators of the intracellular messenger H(2)O(2), and protein chaperones. Antioxid Redox Signal 15(3):781–794. doi:10.1089/ars.2010.3393

    CAS  PubMed  Google Scholar 

  145. Riddell JR, Maier P, Sass SN, Moser MT, Foster BA, Gollnick SO (2012) Peroxiredoxin 1 stimulates endothelial cell expression of VEGF via TLR4 dependent activation of HIF-1alpha. PLoS One 7(11):e50394. doi:10.1371/journal.pone.0050394

    CAS  PubMed Central  PubMed  Google Scholar 

  146. Kisucka J, Chauhan AK, Patten IS, Yesilaltay A, Neumann C, Van Etten RA, Krieger M, Wagner DD (2008) Peroxiredoxin1 prevents excessive endothelial activation and early atherosclerosis. Circ Res 103(6):598–605. doi:10.1161/CIRCRESAHA.108.174870

    CAS  PubMed  Google Scholar 

  147. Park JG, Yoo JY, Jeong SJ, Choi JH, Lee MR, Lee MN, Hwa Lee J, Kim HC, Jo H, Yu DY, Kang SW, Rhee SG, Lee MH, Oh GT (2011) Peroxiredoxin 2 deficiency exacerbates atherosclerosis in apolipoprotein E-deficient mice. Circ Res 109(7):739–749. doi:10.1161/CIRCRESAHA.111.245530

    CAS  PubMed  Google Scholar 

  148. Kang DH, Lee DJ, Kim J, Lee JY, Kim HW, Kwon K, Taylor WR, Jo H, Kang SW (2013) Vascular injury involves the overoxidation of peroxiredoxin type II and is recovered by the peroxiredoxin activity mimetic that induces reendothelialization. Circulation 128(8):834–844. doi:10.1161/CIRCULATIONAHA.113.001725

    CAS  PubMed  Google Scholar 

  149. Randall LM, Ferrer-Sueta G, Denicola A (2013) Peroxiredoxins as preferential targets in H2O2-induced signaling. Methods Enzymol 527:41–63. doi:10.1016/B978-0-12-405882-8.00003-9

    CAS  PubMed  Google Scholar 

  150. Kang DH, Lee DJ, Lee KW, Park YS, Lee JY, Lee SH, Koh YJ, Koh GY, Choi C, Yu DY, Kim J, Kang SW (2011) Peroxiredoxin II is an essential antioxidant enzyme that prevents the oxidative inactivation of VEGF receptor-2 in vascular endothelial cells. Mol Cell 44(4):545–558. doi:10.1016/j.molcel.2011.08.040

    CAS  PubMed  Google Scholar 

  151. Mowbray AL, Kang DH, Rhee SG, Kang SW, Jo H (2008) Laminar shear stress up-regulates peroxiredoxins (PRX) in endothelial cells: PRX 1 as a mechanosensitive antioxidant. J Biol Chem 283(3):1622–1627. doi:10.1074/jbc.M707985200

    CAS  PubMed  Google Scholar 

  152. Riddell JR, Bshara W, Moser MT, Spernyak JA, Foster BA, Gollnick SO (2011) Peroxiredoxin 1 controls prostate cancer growth through Toll-like receptor 4-dependent regulation of tumor vasculature. Cancer Res 71(5):1637–1646. doi:10.1158/0008-5472.CAN-10-3674

    CAS  PubMed Central  PubMed  Google Scholar 

  153. Tao RR, Wang H, Hong LJ, Huang JY, Lu YM, Liao MH, Ye WF, Lu NN, Zhu DY, Huang Q, Fukunaga K, Lou YJ, Shoji I, Wilcox CS, Lai EY, Han F (2014) Nitrosative stress induces peroxiredoxin 1 ubiquitination during ischemic insult via E6AP activation in endothelial cells both in vitro and in vivo. Antioxid Redox Signal 21(1):1–16. doi:10.1089/ars.2013.5381

    CAS  PubMed Central  PubMed  Google Scholar 

  154. Stacey MM, Vissers MC, Winterbourn CC (2012) Oxidation of 2-cys peroxiredoxins in human endothelial cells by hydrogen peroxide, hypochlorous acid, and chloramines. Antioxid Redox Signal 17(3):411–421. doi:10.1089/ars.2011.4348

    CAS  PubMed  Google Scholar 

  155. Mieyal JJ, Chock PB (2012) Posttranslational modification of cysteine in redox signaling and oxidative stress: focus on s-glutathionylation. Antioxid Redox Signal 16(6):471–475. doi:10.1089/ars.2011.4454

    CAS  PubMed Central  PubMed  Google Scholar 

  156. Zhang H, Forman HJ (2012) Glutathione synthesis and its role in redox signaling. Semin Cell Dev Biol 23(7):722–728. doi:10.1016/j.semcdb.2012.03.017

    CAS  PubMed Central  PubMed  Google Scholar 

  157. Langston W, Chidlow JH Jr, Booth BA, Barlow SC, Lefer DJ, Patel RP, Kevil CG (2007) Regulation of endothelial glutathione by ICAM-1 governs VEGF-A-mediated eNOS activity and angiogenesis. Free Radic Biol Med 42(5):720–729. doi:10.1016/j.freeradbiomed.2006.12.010

    CAS  PubMed Central  PubMed  Google Scholar 

  158. Tajima M, Kurashima Y, Sugiyama K, Ogura T, Sakagami H (2009) The redox state of glutathione regulates the hypoxic induction of HIF-1. Eur J Pharmacol 606(1–3):45–49. doi:10.1016/j.ejphar.2009.01.026

    CAS  PubMed  Google Scholar 

  159. Abdelsaid MA, El-Remessy AB (2012) S-glutathionylation of LMW-PTP regulates VEGF-mediated FAK activation and endothelial cell migration. J Cell Sci 125(Pt 20):4751–4760. doi:10.1242/jcs.103481

    CAS  PubMed  Google Scholar 

  160. Murdoch CE, Shuler M, Haeussler DJ, Kikuchi R, Bearelly P, Han J, Watanabe Y, Fuster JJ, Walsh K, Ho YS, Bachschmid MM, Cohen RA, Matsui R (2014) Glutaredoxin-1 up-regulation induces soluble vascular endothelial growth factor receptor 1, attenuating post-ischemia limb revascularization. J Biol Chem 289(12):8633–8644. doi:10.1074/jbc.M113.517219

    CAS  PubMed Central  PubMed  Google Scholar 

  161. Oelze M, Kroller-Schon S, Steven S, Lubos E, Doppler C, Hausding M, Tobias S, Brochhausen C, Li H, Torzewski M, Wenzel P, Bachschmid M, Lackner KJ, Schulz E, Munzel T, Daiber A (2014) Glutathione peroxidase-1 deficiency potentiates dysregulatory modifications of endothelial nitric oxide synthase and vascular dysfunction in aging. Hypertension 63(2):390–396. doi:10.1161/HYPERTENSIONAHA.113.01602

    CAS  PubMed  Google Scholar 

  162. Speciale A, Anwar S, Ricciardi E, Chirafisi J, Saija A, Cimino F (2011) Cellular adaptive response to glutathione depletion modulates endothelial dysfunction triggered by TNF-alpha. Toxicol Lett 207(3):291–297. doi:10.1016/j.toxlet.2011.09.017

    CAS  PubMed  Google Scholar 

  163. Song J, Kang SM, Lee WT, Park KA, Lee KM, Lee JE (2014) Glutathione protects brain endothelial cells from hydrogen peroxide-induced oxidative stress by increasing nrf2 expression. Exp Neurobiol 23(1):93–103. doi:10.5607/en.2014.23.1.93

    CAS  PubMed Central  PubMed  Google Scholar 

  164. Zhou HG, Liu L, Zhang Y, Huang YY, Tao YH, Zhang S, Su JJ, Tang YP, Guo ZL, Hu RM, Dong Q (2013) Glutathione prevents free fatty acids-induced oxidative stress and apoptosis in human brain vascular endothelial cells through Akt pathway. CNS Neurosci Ther 19(4):252–261. doi:10.1111/cns.12068

    PubMed  Google Scholar 

  165. Bir SC, Shen X, Kavanagh TJ, Kevil CG, Pattillo CB (2013) Control of angiogenesis dictated by picomolar superoxide levels. Free Radic Biol Med 63:135–142. doi:10.1016/j.freeradbiomed.2013.05.015

    CAS  PubMed Central  PubMed  Google Scholar 

  166. Caliceti C, Zambonin L, Rizzo B, Fiorentini D, Vieceli Dalla Sega F, Hrelia S, Prata C (2014) Role of plasma membrane caveolae/lipid rafts in VEGF-induced redox signaling in human leukemia cells. BioMed Res Int 2014:857504. doi:10.1155/2014/857504

    PubMed Central  PubMed  Google Scholar 

  167. Oshikawa J, Urao N, Kim HW, Kaplan N, Razvi M, McKinney R, Poole LB, Fukai T, Ushio-Fukai M (2010) Extracellular SOD-derived H2O2 promotes VEGF signaling in caveolae/lipid rafts and post-ischemic angiogenesis in mice. PLoS One 5(4):e10189. doi:10.1371/journal.pone.0010189

    PubMed Central  PubMed  Google Scholar 

  168. Oshikawa J, Kim SJ, Furuta E, Caliceti C, Chen GF, McKinney RD, Kuhr F, Levitan I, Fukai T, Ushio-Fukai M (2012) Novel role of p66Shc in ROS-dependent VEGF signaling and angiogenesis in endothelial cells. Am J Physiol Heart Circ Physiol 302(3):H724–H732. doi:10.1152/ajpheart.00739.2011

    CAS  PubMed Central  PubMed  Google Scholar 

  169. Maraldi T, Prata C, Caliceti C, Vieceli Dalla Sega F, Zambonin L, Fiorentini D, Hakim G (2010) VEGF-induced ROS generation from NAD(P)H oxidases protects human leukemic cells from apoptosis. Int J Oncol 36(6):1581–1589

    CAS  PubMed  Google Scholar 

  170. Zhuang J, Jiang T, Lu D, Luo Y, Zheng C, Feng J, Yang D, Chen C, Yan X (2010) NADPH oxidase 4 mediates reactive oxygen species induction of CD146 dimerization in VEGF signal transduction. Free Radic Biol Med 49(2):227–236. doi:10.1016/j.freeradbiomed.2010.04.007

    CAS  PubMed  Google Scholar 

  171. Evangelista AM, Thompson MD, Bolotina VM, Tong X, Cohen RA (2012) Nox4- and Nox2-dependent oxidant production is required for VEGF-induced SERCA cysteine-674 S-glutathiolation and endothelial cell migration. Free Radic Biol Med 53(12):2327–2334. doi:10.1016/j.freeradbiomed.2012.10.546

    CAS  PubMed  Google Scholar 

  172. Garrido-Urbani S, Jemelin S, Deffert C, Carnesecchi S, Basset O, Szyndralewiez C, Heitz F, Page P, Montet X, Michalik L, Arbiser J, Ruegg C, Krause KH, Imhof BA (2011) Targeting vascular NADPH oxidase 1 blocks tumor angiogenesis through a PPARalpha mediated mechanism. PLoS One 6(2):e14665. doi:10.1371/journal.pone.0014665

    CAS  PubMed Central  PubMed  Google Scholar 

  173. Wang J, Hong Z, Zeng C, Yu Q, Wang H (2014) NADPH oxidase 4 promotes cardiac microvascular angiogenesis after hypoxia/reoxygenation in vitro. Free Radic Biol Med 69:278–288. doi:10.1016/j.freeradbiomed.2014.01.027

    CAS  PubMed  Google Scholar 

  174. Li Q, Fu GB, Zheng JT, He J, Niu XB, Chen QD, Yin Y, Qian X, Xu Q, Wang M, Sun AF, Shu Y, Rui H, Liu LZ, Jiang BH (2013) NADPH oxidase subunit p22(phox)-mediated reactive oxygen species contribute to angiogenesis and tumor growth through AKT and ERK1/2 signaling pathways in prostate cancer. Biochim Biophys Acta 1833(12):3375–3385. doi:10.1016/j.bbamcr.2013.09.018

    CAS  PubMed  Google Scholar 

  175. Sun J, Xu Y, Sun S, Sun Y, Wang X (2010) Intermittent high glucose enhances cell proliferation and VEGF expression in retinal endothelial cells: the role of mitochondrial reactive oxygen species. Mol Cell Biochem 343(1–2):27–35. doi:10.1007/s11010-010-0495-5

    CAS  PubMed  Google Scholar 

  176. Wang Y, Zang QS, Liu Z, Wu Q, Maass D, Dulan G, Shaul PW, Melito L, Frantz DE, Kilgore JA, Williams NS, Terada LS, Nwariaku FE (2011) Regulation of VEGF-induced endothelial cell migration by mitochondrial reactive oxygen species. Am J Physiol Cell Physiol 301(3):C695–C704. doi:10.1152/ajpcell.00322.2010

    CAS  PubMed Central  PubMed  Google Scholar 

  177. Chakrabarti S, Rizvi M, Morin K, Garg R, Freedman JE (2010) The role of CD40L and VEGF in the modulation of angiogenesis and inflammation. Vascul Pharmacol 53(3–4):130–137. doi:10.1016/j.vph.2010.05.003

    CAS  PubMed  Google Scholar 

  178. Stanley AC, Wong CX, Micaroni M, Venturato J, Khromykh T, Stow JL, Lacy P (2014) The Rho GTPase Rac1 is required for recycling endosome-mediated secretion of TNF in macrophages. Immunol Cell Biol 92(3):275–286. doi:10.1038/icb.2013.90

    CAS  PubMed  Google Scholar 

  179. Zhang H, Park Y, Wu J, Chen X, Lee S, Yang J, Dellsperger KC, Zhang C (2009) Role of TNF-alpha in vascular dysfunction. Clin Sci (Lond) 116(3):219–230. doi:10.1042/CS20080196

    CAS  Google Scholar 

  180. Miki H, Funato Y (2012) Regulation of intracellular signalling through cysteine oxidation by reactive oxygen species. J Biochem 151(3):255–261. doi:10.1093/jb/mvs006

    CAS  PubMed  Google Scholar 

  181. Boivin B, Yang M, Tonks NK (2010) Targeting the reversibly oxidized protein tyrosine phosphatase superfamily. Sci Signal 3(137):pl2. doi:10.1126/scisignal.3137pl2

  182. Chen YY, Chu HM, Pan KT, Teng CH, Wang DL, Wang AH, Khoo KH, Meng TC (2008) Cysteine S-nitrosylation protects protein-tyrosine phosphatase 1B against oxidation-induced permanent inactivation. J Biol Chem 283(50):35265–35272. doi:10.1074/jbc.M805287200

    CAS  PubMed Central  PubMed  Google Scholar 

  183. Schwertassek U, Haque A, Krishnan N, Greiner R, Weingarten L, Dick TP, Tonks NK (2014) Reactivation of oxidized PTP1B and PTEN by thioredoxin 1. FEBS J 281(16):3545–3558. doi:10.1111/febs.12898

    CAS  PubMed Central  PubMed  Google Scholar 

  184. Connor KM, Subbaram S, Regan KJ, Nelson KK, Mazurkiewicz JE, Bartholomew PJ, Aplin AE, Tai YT, Aguirre-Ghiso J, Flores SC, Melendez JA (2005) Mitochondrial H2O2 regulates the angiogenic phenotype via PTEN oxidation. J Biol Chem 280(17):16916–16924. doi:10.1074/jbc.M410690200

    CAS  PubMed  Google Scholar 

  185. Juarez JC, Manuia M, Burnett ME, Betancourt O, Boivin B, Shaw DE, Tonks NK, Mazar AP, Donate F (2008) Superoxide dismutase 1 (SOD1) is essential for H2O2-mediated oxidation and inactivation of phosphatases in growth factor signaling. Proc Natl Acad Sci USA 105(20):7147–7152. doi:10.1073/pnas.0709451105

    CAS  PubMed Central  PubMed  Google Scholar 

  186. Frijhoff J, Dagnell M, Augsten M, Beltrami E, Giorgio M, Ostman A (2014) The mitochondrial reactive oxygen species regulator p66Shc controls PDGF-induced signaling and migration through protein tyrosine phosphatase oxidation. Free Radic Biol Med 68:268–277. doi:10.1016/j.freeradbiomed.2013.12.022

    CAS  PubMed  Google Scholar 

  187. Dagnell M, Frijhoff J, Pader I, Augsten M, Boivin B, Xu J, Mandal PK, Tonks NK, Hellberg C, Conrad M, Arner ES, Ostman A (2013) Selective activation of oxidized PTP1B by the thioredoxin system modulates PDGF-beta receptor tyrosine kinase signaling. Proc Natl Acad Sci USA 110(33):13398–13403. doi:10.1073/pnas.1302891110

    CAS  PubMed Central  PubMed  Google Scholar 

  188. Frijhoff J, Dagnell M, Godfrey R, Ostman A (2014) Regulation of protein tyrosine phosphatase oxidation in cell adhesion and migration. Antioxid Redox Signal 20(13):1994–2010. doi:10.1089/ars.2013.5643

    CAS  PubMed  Google Scholar 

  189. Mondol AS, Tonks NK, Kamata T (2014) Nox4 redox regulation of PTP1B contributes to the proliferation and migration of glioblastoma cells by modulating tyrosine phosphorylation of coronin-1C. Free Radic Biol Med 67:285–291. doi:10.1016/j.freeradbiomed.2013.11.005

    CAS  PubMed  Google Scholar 

  190. Hiraga R, Kato M, Miyagawa S, Kamata T (2013) Nox4-derived ROS signaling contributes to TGF-beta-induced epithelial-mesenchymal transition in pancreatic cancer cells. Anticancer Res 33(10):4431–4438

    CAS  PubMed  Google Scholar 

  191. Corcoran A, Cotter TG (2013) Redox regulation of protein kinases. FEBS J 280(9):1944–1965. doi:10.1111/febs.12224

    CAS  PubMed  Google Scholar 

  192. Giannoni E, Buricchi F, Raugei G, Ramponi G, Chiarugi P (2005) Intracellular reactive oxygen species activate Src tyrosine kinase during cell adhesion and anchorage-dependent cell growth. Mol Cell Biol 25(15):6391–6403. doi:10.1128/MCB.25.15.6391-6403.2005

    CAS  PubMed Central  PubMed  Google Scholar 

  193. Truong TH, Carroll KS (2013) Redox regulation of protein kinases. Crit Rev Biochem Mol Biol 48(4):332–356. doi:10.3109/10409238.2013.790873

    CAS  PubMed Central  PubMed  Google Scholar 

  194. Lee M, Choy WC, Abid MR (2011) Direct sensing of endothelial oxidants by vascular endothelial growth factor receptor-2 and c-Src. PLoS One 6(12):e28454. doi:10.1371/journal.pone.0028454

    CAS  PubMed Central  PubMed  Google Scholar 

  195. Gianni D, Taulet N, DerMardirossian C, Bokoch GM (2010) c-Src-mediated phosphorylation of NoxA1 and Tks4 induces the reactive oxygen species (ROS)-dependent formation of functional invadopodia in human colon cancer cells. Mol Biol Cell 21(23):4287–4298. doi:10.1091/mbc.E10-08-0685

    CAS  PubMed Central  PubMed  Google Scholar 

  196. Giannoni E, Chiarugi P (2014) Redox circuitries driving Src regulation. Antioxid Redox Signal 20(13):2011–2025. doi:10.1089/ars.2013.5525

    CAS  PubMed  Google Scholar 

  197. Xi G, Shen X, Maile LA, Wai C, Gollahon K, Clemmons DR (2012) Hyperglycemia enhances IGF-I-stimulated Src activation via increasing Nox4-derived reactive oxygen species in a PKCzeta-dependent manner in vascular smooth muscle cells. Diabetes 61(1):104–113. doi:10.2337/db11-0990

    CAS  PubMed Central  PubMed  Google Scholar 

  198. Son Y, Kim S, Chung HT, Pae HO (2013) Reactive oxygen species in the activation of MAP kinases. Methods Enzymol 528:27–48. doi:10.1016/B978-0-12-405881-1.00002-1

    CAS  PubMed  Google Scholar 

  199. Breton-Romero R, Lamas S (2013) Hydrogen peroxide signaling mediator in the activation of p38 MAPK in vascular endothelial cells. Methods Enzymol 528:49–59. doi:10.1016/B978-0-12-405881-1.00003-3

    CAS  PubMed  Google Scholar 

  200. Galli S, Antico Arciuch VG, Poderoso C, Converso DP, Zhou Q, de Kier Bal, Joffe E, Cadenas E, Boczkowski J, Carreras MC, Poderoso JJ (2008) Tumor cell phenotype is sustained by selective MAPK oxidation in mitochondria. PLoS One 3(6):e2379. doi:10.1371/journal.pone.0002379

    PubMed Central  PubMed  Google Scholar 

  201. Rajashekhar G, Kamocka M, Marin A, Suckow MA, Wolter WR, Badve S, Sanjeevaiah AR, Pumiglia K, Rosen E, Clauss M (2011) Pro-inflammatory angiogenesis is mediated by p38 MAP kinase. J Cell Physiol 226(3):800–808. doi:10.1002/jcp.22404

    CAS  PubMed  Google Scholar 

  202. Yan F, Wang Y, Wu X, Peshavariya HM, Dusting GJ, Zhang M, Jiang F (2014) Nox4 and redox signaling mediate TGF-beta-induced endothelial cell apoptosis and phenotypic switch. Cell Death Dis 5:e1010. doi:10.1038/cddis.2013.551

    CAS  PubMed Central  PubMed  Google Scholar 

  203. Cosentino-Gomes D, Rocco-Machado N, Meyer-Fernandes JR (2012) Cell signaling through protein kinase C oxidation and activation. Int J Mol Sci 13(9):10697–10721. doi:10.3390/ijms130910697

    CAS  PubMed Central  PubMed  Google Scholar 

  204. Giorgi C, Agnoletto C, Baldini C, Bononi A, Bonora M, Marchi S, Missiroli S, Patergnani S, Poletti F, Rimessi A, Zavan B, Pinton P (2010) Redox control of protein kinase C: cell- and disease-specific aspects. Antioxid Redox Signal 13(7):1051–1085. doi:10.1089/ars.2009.2825

    CAS  PubMed  Google Scholar 

  205. Burgoyne JR, Eaton P (2013) Detecting disulfide-bound complexes and the oxidative regulation of cyclic nucleotide-dependent protein kinases by H2O2. Methods Enzymol 528:111–128. doi:10.1016/B978-0-12-405881-1.00007-0

    CAS  PubMed  Google Scholar 

  206. Ushio-Fukai M, Alexander RW, Akers M, Yin Q, Fujio Y, Walsh K, Griendling KK (1999) Reactive oxygen species mediate the activation of Akt/protein kinase B by angiotensin II in vascular smooth muscle cells. J Biol Chem 274(32):22699–22704

    CAS  PubMed  Google Scholar 

  207. Wani R, Qian J, Yin L, Bechtold E, King SB, Poole LB, Paek E, Tsang AW, Furdui CM (2011) Isoform-specific regulation of Akt by PDGF-induced reactive oxygen species. Proc Natl Acad Sci USA 108(26):10550–10555. doi:10.1073/pnas.1011665108

    CAS  PubMed Central  PubMed  Google Scholar 

  208. Yasukawa T, Tokunaga E, Ota H, Sugita H, Martyn JA, Kaneki M (2005) S-nitrosylation-dependent inactivation of Akt/protein kinase B in insulin resistance. J Biol Chem 280(9):7511–7518. doi:10.1074/jbc.M411871200

    CAS  PubMed  Google Scholar 

  209. Pei DS, Song YJ, Yu HM, Hu WW, Du Y, Zhang GY (2008) Exogenous nitric oxide negatively regulates c-Jun N-terminal kinase activation via inhibiting endogenous NO-induced S-nitrosylation during cerebral ischemia and reperfusion in rat hippocampus. J Neurochem 106(4):1952–1963. doi:10.1111/j.1471-4159.2008.05531.x

    CAS  PubMed  Google Scholar 

  210. Zmijewski JW, Banerjee S, Bae H, Friggeri A, Lazarowski ER, Abraham E (2010) Exposure to hydrogen peroxide induces oxidation and activation of AMP-activated protein kinase. J Biol Chem 285(43):33154–33164. doi:10.1074/jbc.M110.143685

    CAS  PubMed Central  PubMed  Google Scholar 

  211. Cardaci S, Filomeni G, Ciriolo MR (2012) Redox implications of AMPK-mediated signal transduction beyond energetic clues. J Cell Sci 125(Pt 9):2115–2125. doi:10.1242/jcs.095216

    CAS  PubMed  Google Scholar 

  212. Burgoyne JR, Oka S, Ale-Agha N, Eaton P (2013) Hydrogen peroxide sensing and signaling by protein kinases in the cardiovascular system. Antioxid Redox Signal 18(9):1042–1052. doi:10.1089/ars.2012.4817

    CAS  PubMed Central  PubMed  Google Scholar 

  213. Mungai PT, Waypa GB, Jairaman A, Prakriya M, Dokic D, Ball MK, Schumacker PT (2011) Hypoxia triggers AMPK activation through reactive oxygen species-mediated activation of calcium release-activated calcium channels. Mol Cell Biol 31(17):3531–3545. doi:10.1128/MCB.05124-11

    CAS  PubMed Central  PubMed  Google Scholar 

  214. Wang Q, Liang B, Shirwany NA, Zou MH (2011) 2-Deoxy-d-glucose treatment of endothelial cells induces autophagy by reactive oxygen species-mediated activation of the AMP-activated protein kinase. PLoS One 6(2):e17234. doi:10.1371/journal.pone.0017234

    CAS  PubMed Central  PubMed  Google Scholar 

  215. Nakashima I, Kato M, Akhand AA, Suzuki H, Takeda K, Hossain K, Kawamoto Y (2002) Redox-linked signal transduction pathways for protein tyrosine kinase activation. Antioxid Redox Signal 4(3):517–531. doi:10.1089/15230860260196326

    CAS  PubMed  Google Scholar 

  216. Catarzi S, Biagioni C, Giannoni E, Favilli F, Marcucci T, Iantomasi T, Vincenzini MT (2005) Redox regulation of platelet-derived-growth-factor-receptor: role of NADPH-oxidase and c-Src tyrosine kinase. Biochim Biophys Acta 1745(2):166–175. doi:10.1016/j.bbamcr.2005.03.004

    CAS  PubMed  Google Scholar 

  217. Bouzigues CI, Nguyen TL, Ramodiharilafy R, Claeson A, Tharaux PL, Alexandrou A (2014) Regulation of the ROS response dynamics and organization to PDGF motile stimuli revealed by single nanoparticle imaging. Chem Biol 21(5):647–656. doi:10.1016/j.chembiol.2014.02.020

    CAS  PubMed  Google Scholar 

  218. Bashan N, Kovsan J, Kachko I, Ovadia H, Rudich A (2009) Positive and negative regulation of insulin signaling by reactive oxygen and nitrogen species. Physiol Rev 89(1):27–71. doi:10.1152/physrev.00014.2008

    CAS  PubMed  Google Scholar 

  219. Goldstein BJ, Mahadev K, Wu X, Zhu L, Motoshima H (2005) Role of insulin-induced reactive oxygen species in the insulin signaling pathway. Antioxid Redox Signal 7(7–8):1021–1031. doi:10.1089/ars.2005.7.1021

    CAS  PubMed Central  PubMed  Google Scholar 

  220. Iwakami S, Misu H, Takeda T, Sugimori M, Matsugo S, Kaneko S, Takamura T (2011) Concentration-dependent dual effects of hydrogen peroxide on insulin signal transduction in H4IIEC hepatocytes. PLoS One 6(11):e27401. doi:10.1371/journal.pone.0027401

    CAS  PubMed Central  PubMed  Google Scholar 

  221. Woo HA, Yim SH, Shin DH, Kang D, Yu DY, Rhee SG (2010) Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. Cell 140(4):517–528. doi:10.1016/j.cell.2010.01.009

    CAS  PubMed  Google Scholar 

  222. Paulsen CE, Truong TH, Garcia FJ, Homann A, Gupta V, Leonard SE, Carroll KS (2012) Peroxide-dependent sulfenylation of the EGFR catalytic site enhances kinase activity. Nat Chem Biol 8(1):57–64. doi:10.1038/nchembio.736

    CAS  Google Scholar 

  223. Gonzalez-Pacheco FR, Deudero JJ, Castellanos MC, Castilla MA, Alvarez-Arroyo MV, Yague S, Caramelo C (2006) Mechanisms of endothelial response to oxidative aggression: protective role of autologous VEGF and induction of VEGFR2 by H2O2. Am J Physiol Heart Circ Physiol 291(3):H1395–H1401. doi:10.1152/ajpheart.01277.2005

    CAS  PubMed  Google Scholar 

  224. Ushio-Fukai M (2007) VEGF signaling through NADPH oxidase-derived ROS. Antioxid Redox Signal 9(6):731–739. doi:10.1089/ars.2007.1556

    CAS  PubMed  Google Scholar 

  225. Nakamura Y, Patrushev N, Inomata H, Mehta D, Urao N, Kim HW, Razvi M, Kini V, Mahadev K, Goldstein BJ, McKinney R, Fukai T, Ushio-Fukai M (2008) Role of protein tyrosine phosphatase 1B in vascular endothelial growth factor signaling and cell-cell adhesions in endothelial cells. Circ Res 102(10):1182–1191. doi:10.1161/CIRCRESAHA.107.167080

    CAS  PubMed Central  PubMed  Google Scholar 

  226. Boivin B, Zhang S, Arbiser JL, Zhang ZY, Tonks NK (2008) A modified cysteinyl-labeling assay reveals reversible oxidation of protein tyrosine phosphatases in angiomyolipoma cells. Proc Natl Acad Sci USA 105(29):9959–9964. doi:10.1073/pnas.0804336105

    CAS  PubMed Central  PubMed  Google Scholar 

  227. Kemble DJ, Sun G (2009) Direct and specific inactivation of protein tyrosine kinases in the Src and FGFR families by reversible cysteine oxidation. Proc Natl Acad Sci USA 106(13):5070–5075. doi:10.1073/pnas.0806117106

    CAS  PubMed Central  PubMed  Google Scholar 

  228. Thomas SR, Witting PK, Drummond GR (2008) Redox control of endothelial function and dysfunction: molecular mechanisms and therapeutic opportunities. Antioxid Redox Signal 10(10):1713–1765. doi:10.1089/ars.2008.2027

    CAS  PubMed  Google Scholar 

  229. Semenza GL (2014) Hypoxia-inducible factor 1 and cardiovascular disease. Annu Rev Physiol 76:39–56. doi:10.1146/annurev-physiol-021113-170322

    CAS  PubMed  Google Scholar 

  230. Li F, Sonveaux P, Rabbani ZN, Liu S, Yan B, Huang Q, Vujaskovic Z, Dewhirst MW, Li CY (2007) Regulation of HIF-1alpha stability through S-nitrosylation. Mol Cell 26(1):63–74. doi:10.1016/j.molcel.2007.02.024

    PubMed Central  PubMed  Google Scholar 

  231. Lima B, Lam GK, Xie L, Diesen DL, Villamizar N, Nienaber J, Messina E, Bowles D, Kontos CD, Hare JM, Stamler JS, Rockman HA (2009) Endogenous S-nitrosothiols protect against myocardial injury. Proc Natl Acad Sci USA 106(15):6297–6302. doi:10.1073/pnas.0901043106

    CAS  PubMed Central  PubMed  Google Scholar 

  232. Kietzmann T, Gorlach A (2005) Reactive oxygen species in the control of hypoxia-inducible factor-mediated gene expression. Semin Cell Dev Biol 16(4–5):474–486. doi:10.1016/j.semcdb.2005.03.010

    CAS  PubMed  Google Scholar 

  233. Jung SN, Yang WK, Kim J, Kim HS, Kim EJ, Yun H, Park H, Kim SS, Choe W, Kang I, Ha J (2008) Reactive oxygen species stabilize hypoxia-inducible factor-1 alpha protein and stimulate transcriptional activity via AMP-activated protein kinase in DU145 human prostate cancer cells. Carcinogenesis 29(4):713–721. doi:10.1093/carcin/bgn032

    CAS  PubMed  Google Scholar 

  234. Comito G, Calvani M, Giannoni E, Bianchini F, Calorini L, Torre E, Migliore C, Giordano S, Chiarugi P (2011) HIF-1alpha stabilization by mitochondrial ROS promotes Met-dependent invasive growth and vasculogenic mimicry in melanoma cells. Free Radic Biol Med 51(4):893–904. doi:10.1016/j.freeradbiomed.2011.05.042

    CAS  PubMed  Google Scholar 

  235. Calvani M, Comito G, Giannoni E, Chiarugi P (2012) Time-dependent stabilization of hypoxia inducible factor-1alpha by different intracellular sources of reactive oxygen species. PLoS One 7(10):e38388. doi:10.1371/journal.pone.0038388

    CAS  PubMed Central  PubMed  Google Scholar 

  236. Hoesel B, Schmid JA (2013) The complexity of NF-kappaB signaling in inflammation and cancer. Mol Cancer 12:86. doi:10.1186/1476-4598-12-86

    CAS  PubMed Central  PubMed  Google Scholar 

  237. Morgan MJ, Liu ZG (2011) Crosstalk of reactive oxygen species and NF-kappaB signaling. Cell Res 21(1):103–115. doi:10.1038/cr.2010.178

    CAS  PubMed Central  PubMed  Google Scholar 

  238. Gloire G, Piette J (2009) Redox regulation of nuclear post-translational modifications during NF-kappaB activation. Antioxid Redox Signal 11(9):2209–2222. doi:10.1089/ARS.2009.2463

    CAS  PubMed  Google Scholar 

  239. Madamanchi NR, Runge MS (2013) Redox signaling in cardiovascular health and disease. Free Radic Biol Med 61:473–501. doi:10.1016/j.freeradbiomed.2013.04.001

    CAS  PubMed  Google Scholar 

  240. Reynaert NL, van der Vliet A, Guala AS, McGovern T, Hristova M, Pantano C, Heintz NH, Heim J, Ho YS, Matthews DE, Wouters EF, Janssen-Heininger YM (2006) Dynamic redox control of NF-kappaB through glutaredoxin-regulated S-glutathionylation of inhibitory kappaB kinase beta. Proc Natl Acad Sci USA 103(35):13086–13091. doi:10.1073/pnas.0603290103

    CAS  PubMed Central  PubMed  Google Scholar 

  241. Hajra L, Evans AI, Chen M, Hyduk SJ, Collins T, Cybulsky MI (2000) The NF-kappa B signal transduction pathway in aortic endothelial cells is primed for activation in regions predisposed to atherosclerotic lesion formation. Proc Natl Acad Sci USA 97(16):9052–9057

    CAS  PubMed Central  PubMed  Google Scholar 

  242. DangLi R, HeKong W, JiQin L, MingHua Z, WenCheng Z (2012) ROS-induced ZNF580 expression: a key role for H2O2/NF-kappaB signaling pathway in vascular endothelial inflammation. Mol Cell Biochem 359(1–2):183–191. doi:10.1007/s11010-011-1013-0

    PubMed  Google Scholar 

  243. Kassan M, Choi SK, Galan M, Bishop A, Umezawa K, Trebak M, Belmadani S, Matrougui K (2013) Enhanced NF-kappaB activity impairs vascular function through PARP-1-, SP-1-, and COX-2-dependent mechanisms in type 2 diabetes. Diabetes 62(6):2078–2087. doi:10.2337/db12-1374

    CAS  PubMed Central  PubMed  Google Scholar 

  244. Aurora AB, Biyashev D, Mirochnik Y, Zaichuk TA, Sanchez-Martinez C, Renault MA, Losordo D, Volpert OV (2010) NF-kappaB balances vascular regression and angiogenesis via chromatin remodeling and NFAT displacement. Blood 116(3):475–484. doi:10.1182/blood-2009-07-232132

    CAS  PubMed Central  PubMed  Google Scholar 

  245. Fourquet S, Guerois R, Biard D, Toledano MB (2010) Activation of NRF2 by nitrosative agents and H2O2 involves KEAP1 disulfide formation. J Biol Chem 285(11):8463–8471. doi:10.1074/jbc.M109.051714

    CAS  PubMed Central  PubMed  Google Scholar 

  246. Chen XL, Dodd G, Thomas S, Zhang X, Wasserman MA, Rovin BH, Kunsch C (2006) Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression. Am J Physiol Heart Circ Physiol 290(5):H1862–H1870. doi:10.1152/ajpheart.00651.2005

    CAS  PubMed  Google Scholar 

  247. Valcarcel-Ares MN, Gautam T, Warrington JP, Bailey-Downs L, Sosnowska D, de Cabo R, Losonczy G, Sonntag WE, Ungvari Z, Csiszar A (2012) Disruption of Nrf2 signaling impairs angiogenic capacity of endothelial cells: implications for microvascular aging. J Gerontol Ser A Biol Sci Med Sci 67(8):821–829. doi:10.1093/gerona/glr229

    Google Scholar 

  248. Florczyk U, Jazwa A, Maleszewska M, Mendel M, Szade K, Kozakowska M, Grochot-Przeczek A, Viscardi M, Czauderna S, Bukowska-Strakova K, Kotlinowski J, Jozkowicz A, Loboda A, Dulak J (2014) Nrf2 regulates angiogenesis: effect on endothelial cells, bone marrow-derived proangiogenic cells and hind limb ischemia. Antioxid Redox Signal 20(11):1693–1708. doi:10.1089/ars.2013.5219

    CAS  PubMed Central  PubMed  Google Scholar 

  249. Wei Y, Gong J, Thimmulappa RK, Kosmider B, Biswal S, Duh EJ (2013) Nrf2 acts cell-autonomously in endothelium to regulate tip cell formation and vascular branching. Proc Natl Acad Sci USA 110(41):E3910–E3918. doi:10.1073/pnas.1309276110

    CAS  PubMed Central  PubMed  Google Scholar 

  250. Kuang L, Feng J, He G, Jing T (2013) Knockdown of Nrf2 inhibits the angiogenesis of rat cardiac micro-vascular endothelial cells under hypoxic conditions. Int J Biol Sci 9(7):656–665. doi:10.7150/ijbs.5887

    PubMed Central  PubMed  Google Scholar 

  251. Afonyushkin T, Oskolkova OV, Philippova M, Resink TJ, Erne P, Binder BR, Bochkov VN (2010) Oxidized phospholipids regulate expression of ATF4 and VEGF in endothelial cells via NRF2-dependent mechanism: novel point of convergence between electrophilic and unfolded protein stress pathways. Arterioscler Thromb Vasc Biol 30(5):1007–1013. doi:10.1161/ATVBAHA.110.204354

    CAS  PubMed  Google Scholar 

  252. Uno K, Prow TW, Bhutto IA, Yerrapureddy A, McLeod DS, Yamamoto M, Reddy SP, Lutty GA (2010) Role of Nrf2 in retinal vascular development and the vaso-obliterative phase of oxygen-induced retinopathy. Exp Eye Res 90(4):493–500. doi:10.1016/j.exer.2009.12.012

    CAS  PubMed  Google Scholar 

  253. Ji X, Wang H, Zhu J, Zhu L, Pan H, Li W, Zhou Y, Cong Z, Yan F, Chen S (2014) Knockdown of Nrf2 suppresses glioblastoma angiogenesis by inhibiting hypoxia-induced activation of HIF-1alpha. Int J Cancer J Int du Cancer 135(3):574–584. doi:10.1002/ijc.28699

    CAS  Google Scholar 

  254. Kim TH, Hur EG, Kang SJ, Kim JA, Thapa D, Lee YM, Ku SK, Jung Y, Kwak MK (2011) NRF2 blockade suppresses colon tumor angiogenesis by inhibiting hypoxia-induced activation of HIF-1alpha. Cancer Res 71(6):2260–2275. doi:10.1158/0008-5472.CAN-10-3007

    CAS  PubMed  Google Scholar 

  255. Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473(7347):298–307. doi:10.1038/nature10144

    CAS  PubMed Central  PubMed  Google Scholar 

  256. Brakenhielm E, Cao R, Cao Y (2001) Suppression of angiogenesis, tumor growth, and wound healing by resveratrol, a natural compound in red wine and grapes. FASEB J 15(10):1798–1800

    CAS  PubMed  Google Scholar 

  257. Muliyil S, Narasimha M (2014) Mitochondrial ROS regulates cytoskeletal and mitochondrial remodeling to tune cell and tissue dynamics in a model for wound healing. Dev Cell 28(3):239–252. doi:10.1016/j.devcel.2013.12.019

    CAS  PubMed  Google Scholar 

  258. Catalano V, Turdo A, Di Franco S, Dieli F, Todaro M, Stassi G (2013) Tumor and its microenvironment: a synergistic interplay. Semin Cancer Biol 23(6 Pt B):522–532. doi:10.1016/j.semcancer.2013.08.007

  259. Gorrini C, Harris IS, Mak TW (2013) Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discovery 12(12):931–947. doi:10.1038/nrd4002

    CAS  PubMed  Google Scholar 

  260. Okuno Y, Nakamura-Ishizu A, Otsu K, Suda T, Kubota Y (2012) Pathological neoangiogenesis depends on oxidative stress regulation by ATM. Nat Med 18(8):1208–1216. doi:10.1038/nm.2846

    CAS  PubMed  Google Scholar 

  261. Alitalo AK, Proulx ST, Karaman S, Aebischer D, Martino S, Jost M, Schneider N, Bry M, Detmar M (2013) VEGF-C and VEGF-D blockade inhibits inflammatory skin carcinogenesis. Cancer Res 73(14):4212–4221. doi:10.1158/0008-5472.CAN-12-4539

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We apologize to the many researchers whose work was not cited in this review due to space limitations. We would like to thank all members of Santoro laboratory for support and discussion. Work in Santoro’s laboratory is supported by grants from European Community (ERC and Marie Curie IRG), HFSP, Telethon, FWO and AIRC.

Author information

Authors and Affiliations

  1. Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Turin, Italy

    Emiliano Panieri

  2. Laboratory of Endothelial Molecular Biology, Vesalius Research Center, VIB, 3000, Leuven, Belgium

    Massimo M. Santoro

  3. Laboratory of Endothelial Molecular Biology, Department of Oncology, University of Leuven, 3000, Leuven, Belgium

    Massimo M. Santoro

Authors
  1. Emiliano Panieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Massimo M. Santoro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Massimo M. Santoro.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Panieri, E., Santoro, M.M. ROS signaling and redox biology in endothelial cells. Cell. Mol. Life Sci. 72, 3281–3303 (2015). https://doi.org/10.1007/s00018-015-1928-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-015-1928-9

Keywords

Search

Navigation