Cellular and Molecular Life Sciences

, Volume 71, Issue 17, pp 3219–3239

Redox regulation of endothelial cell fate



Endothelial cells (ECs) are present throughout blood vessels and have variable roles in both physiological and pathological settings. EC fate is altered and regulated by several key factors in physiological or pathological conditions. Reactive nitrogen species and reactive oxygen species derived from NAD(P)H oxidases, mitochondria, or nitric oxide-producing enzymes are not only cytotoxic but also compose a signaling network in the redox system. The formation, actions, key molecular interactions, and physiological and pathological relevance of redox signals in ECs remain unclear. We review the identities, sources, and biological actions of oxidants and reductants produced during EC function or dysfunction. Further, we discuss how ECs shape key redox sensors and examine the biological functions, transcriptional responses, and post-translational modifications evoked by the redox system in ECs. We summarize recent findings regarding the mechanisms by which redox signals regulate the fate of ECs and address the outcome of altered EC fate in health and disease. Future studies will examine if the redox biology of ECs can be targeted in pathophysiological conditions.


Redox homeostasis Endothelial cell fate Atherosclerosis Hypertension Cancer Obesity Diabetes 



3-Mercaptopyruvate sulfurtransferase


5-Amino-4-imidazole carboxamide riboside


Adenosine monophosphate-activated protein kinase


Brown adipose tissue




Bone morphogenetic protein




Cystathionine β-synthase




Cystathionine γ-lyase


Eicosapentaenoic acid


Endoplasmic reticulum


Mitochondrial electron-transport chain


Forkhead homeobox type O


Glutathione peroxidase


Glutathione reductase




GTP-cyclohydrolase I


Hydrogen peroxide


Hypoxia-inducible factor 1


Human umbilical vein endothelial cells


Intercellular adhesion molecule-1


IкB kinase


c-Jun N-terminal kinase


Kelch-like ECH-associated protein 1


Low-density lipoprotein receptor


Liver kinase B1


Monocyte chemoattractant protein


Sodium hydrosulfide


Nitric oxide


Nitro-fatty acids


Nitric oxide synthase


NADPH oxidase


Nuclear factor erythroid-2-related factor 2


Superoxide anion


Hypoxia and glucose deprivation




Phosphoinositide 3-kinase




Phosphatase and tensin homolog


Reactive nitrogen species


Reactive oxygen species




Sulfinic acids


Sulfonic acids


Sulfenic acids




Disulfide bonds


Sirtuin 1


Superoxide dismutase


Smooth muscle


Sterol regulatory element binding protein 2


Thromboxane receptor




Vascular endothelial growth factor


VEGF receptor


Vascular cell adhesion molecule-1


White adipose tissue


  1. 1.
    Cines DB, Pollak ES, Buck CA et al (1998) Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 91:3527–3561PubMedGoogle Scholar
  2. 2.
    Dong Y, Zhang M, Liang B et al (2010) Reduction of AMP-activated protein kinase {alpha}2 increases endoplasmic reticulum stress and atherosclerosis in vivo. Circulation 121:792–803PubMedCentralPubMedGoogle Scholar
  3. 3.
    Budhiraja R, Tuder RM, Hassoun PM (2004) Endothelial dysfunction in pulmonary hypertension. Circulation 109:159–165PubMedGoogle Scholar
  4. 4.
    Celermajer DS, Sorensen KE, Spiegelhalter DJ, Georgakopoulos D, Robinson J, Deanfield JE (1994) Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol 24:471–476PubMedGoogle Scholar
  5. 5.
    Stenvinkel P (2001) Endothelial dysfunction and inflammation-is there a link? Nephrol Dial Transpl 16:1968–1971Google Scholar
  6. 6.
    Pasula S, Cai X, Dong Y et al (2012) Endothelial epsin deficiency decreases tumor growth by enhancing VEGF signaling. J Clin Invest 122:4424–4438PubMedCentralPubMedGoogle Scholar
  7. 7.
    Cao Y (2013) Angiogenesis and vascular functions in modulation of obesity, adipose metabolism, and insulin sensitivity. Cell Metab 18:478–489PubMedGoogle Scholar
  8. 8.
    Deanfield JE, Halcox JP, Rabelink TJ (2007) Endothelial function and dysfunction: testing and clinical relevance. Circulation 115:1285–1295PubMedGoogle Scholar
  9. 9.
    Xu J, Zou MH (2009) Molecular insights and therapeutic targets for diabetic endothelial dysfunction. Circulation 120:1266–1286PubMedCentralPubMedGoogle Scholar
  10. 10.
    Zhang DX, Gutterman DD (2007) Mitochondrial reactive oxygen species-mediated signaling in endothelial cells. Am J Physiol Heart Circ Physiol 292:H2023–H2031PubMedGoogle Scholar
  11. 11.
    Cai H (2005) Hydrogen peroxide regulation of endothelial function: origins, mechanisms, and consequences. Cardiovasc Res 68:26–36PubMedGoogle Scholar
  12. 12.
    Beckman JS, Koppenol WH (1996) Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 271:C1424–C1437PubMedGoogle Scholar
  13. 13.
    Pacher P, Beckman JS, Liaudet L (2007) Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87:315–424PubMedCentralPubMedGoogle Scholar
  14. 14.
    Zou MH, Shi C, Cohen RA (2002) High glucose via peroxynitrite causes tyrosine nitration and inactivation of prostacyclin synthase that is associated with thromboxane/prostaglandin H(2) receptor-mediated apoptosis and adhesion molecule expression in cultured human aortic endothelial cells. Diabetes 51:198–203PubMedGoogle Scholar
  15. 15.
    Nie H, Wu JL, Zhang M, Xu J, Zou MH (2006) Endothelial nitric oxide synthase-dependent tyrosine nitration of prostacyclin synthase in diabetes in vivo. Diabetes 55:3133–3141PubMedGoogle Scholar
  16. 16.
    Wang R (2002) Two’s company, three’s a crowd: can H2S be the third endogenous gaseous transmitter? FASEB J 16:1792–1798PubMedGoogle Scholar
  17. 17.
    Mustafa AK, Gadalla MM, Snyder SH (2009) Signaling by gasotransmitters. Sci Signal 2:re2PubMedCentralPubMedGoogle Scholar
  18. 18.
    Wang K, Ahmad S, Cai M et al (2013) Dysregulation of hydrogen sulfide producing enzyme cystathionine gamma-lyase contributes to maternal hypertension and placental abnormalities in preeclampsia. Circulation 127:2514–2522PubMedGoogle Scholar
  19. 19.
    Mani S, Li H, Untereiner A et al (2013) Decreased endogenous production of hydrogen sulfide accelerates atherosclerosis. Circulation 127:2523–2534PubMedGoogle Scholar
  20. 20.
    Szabo C, Coletta C, Chao C et al (2013) Tumor-derived hydrogen sulfide, produced by cystathionine-beta-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer. Proc Natl Acad Sci USA 110:12474–12479PubMedCentralPubMedGoogle Scholar
  21. 21.
    Kabil O, Banerjee R (2014) Enzymology of H2S biogenesis, decay and signaling. Antioxid Redox Signal 20:770–782PubMedGoogle Scholar
  22. 22.
    Modis K, Coletta C, Erdelyi K, Papapetropoulos A, Szabo C (2013) Intramitochondrial hydrogen sulfide production by 3-mercaptopyruvate sulfurtransferase maintains mitochondrial electron flow and supports cellular bioenergetics. FASEB J 27:601–611PubMedGoogle Scholar
  23. 23.
    Yadav PK, Yamada K, Chiku T, Koutmos M, Banerjee R (2013) Structure and kinetic analysis of H2S production by human mercaptopyruvate sulfurtransferase. J Biol Chem 288:20002–20013PubMedCentralPubMedGoogle Scholar
  24. 24.
    Shibuya N, Mikami Y, Kimura Y, Nagahara N, Kimura H (2009) Vascular endothelium expresses 3-mercaptopyruvate sulfurtransferase and produces hydrogen sulfide. J Biochem 146:623–626PubMedGoogle Scholar
  25. 25.
    Tang C, Li X, Du J (2006) Hydrogen sulfide as a new endogenous gaseous transmitter in the cardiovascular system. Curr Vasc Pharmacol 4:17–22PubMedGoogle Scholar
  26. 26.
    Yang G, Wu L, Jiang B et al (2008) H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase. Science 322:587–590PubMedCentralPubMedGoogle Scholar
  27. 27.
    Yang G, Wu L, Wang R (2006) Pro-apoptotic effect of endogenous H2S on human aorta smooth muscle cells. FASEB J 20:553–555PubMedGoogle Scholar
  28. 28.
    Abe K, Kimura H (1996) The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosci 16:1066–1071PubMedGoogle Scholar
  29. 29.
    Beltowski J, Jamroz-Wisniewska A (2012) Modulation of h(2)s metabolism by statins: a new aspect of cardiovascular pharmacology. Antioxid Redox Signal 17:81–94PubMedCentralPubMedGoogle Scholar
  30. 30.
    Olson KR (2012) A practical look at the chemistry and biology of hydrogen sulfide. Antioxid Redox Signal 17:32–44PubMedCentralPubMedGoogle Scholar
  31. 31.
    Greiner R, Palinkas Z, Basell K et al (2013) Polysulfides link H2S to protein thiol oxidation. Antioxid Redox Signal 19:1749–1765PubMedCentralPubMedGoogle Scholar
  32. 32.
    Li L, Whiteman M, Guan YY et al (2008) Characterization of a novel, water-soluble hydrogen sulfide-releasing molecule (GYY4137): new insights into the biology of hydrogen sulfide. Circulation 117:2351–2360PubMedGoogle Scholar
  33. 33.
    Keefe AD, Miller SL, McDonald G, Bada J (1995) Investigation of the prebiotic synthesis of amino acids and RNA bases from CO2 using FeS/H2S as a reducing agent. Proc Natl Acad Sci USA 92:11904–11906PubMedCentralPubMedGoogle Scholar
  34. 34.
    Tyagi N, Moshal KS, Sen U et al (2009) H2S protects against methionine-induced oxidative stress in brain endothelial cells. Antioxid Redox Signal 11:25–33PubMedCentralPubMedGoogle Scholar
  35. 35.
    Kimura H (2014) Production and physiological effects of hydrogen sulfide. Antioxid Redox Signal 20:783–793PubMedGoogle Scholar
  36. 36.
    Collman JP, Ghosh S, Dey A, Decreau RA (2009) Using a functional enzyme model to understand the chemistry behind hydrogen sulfide induced hibernation. Proc Natl Acad Sci USA 106:22090–22095PubMedCentralPubMedGoogle Scholar
  37. 37.
    Szabo G, Veres G, Radovits T et al (2011) Cardioprotective effects of hydrogen sulfide. Nitric Oxide 25:201–210PubMedCentralPubMedGoogle Scholar
  38. 38.
    Wen YD, Wang H, Kho SH et al (2013) Hydrogen sulfide protects HUVECs against hydrogen peroxide induced mitochondrial dysfunction and oxidative stress. PLoS ONE 8:e53147PubMedCentralPubMedGoogle Scholar
  39. 39.
    Cai WJ, Wang MJ, Moore PK, Jin HM, Yao T, Zhu YC (2007) The novel proangiogenic effect of hydrogen sulfide is dependent on Akt phosphorylation. Cardiovasc Res 76:29–40PubMedGoogle Scholar
  40. 40.
    Tao BB, Liu SY, Zhang CC et al (2013) VEGFR2 functions as an H2S-targeting receptor protein kinase with its novel Cys 1045-Cys1024 disulfide bond serving as a specific molecular switch for hydrogen sulfide actions in vascular endothelial cells. Antioxid Redox Signal 19:448–464PubMedCentralPubMedGoogle Scholar
  41. 41.
    Coletta C, Papapetropoulos A, Erdelyi K et al (2012) Hydrogen sulfide and nitric oxide are mutually dependent in the regulation of angiogenesis and endothelium-dependent vasorelaxation. Proc Natl Acad Sci USA 109:9161–9166PubMedCentralPubMedGoogle Scholar
  42. 42.
    Wang MJ, Cai WJ, Li N, Ding YJ, Chen Y, Zhu YC (2010) The hydrogen sulfide donor NaHS promotes angiogenesis in a rat model of hind limb ischemia. Antioxid Redox Signal 12:1065–1077PubMedGoogle Scholar
  43. 43.
    Polhemus DJ, Kondo K, Bhushan S et al (2013) Hydrogen sulfide attenuates cardiac dysfunction after heart failure via induction of angiogenesis. Circ Heart Fail 6:1077–1086PubMedGoogle Scholar
  44. 44.
    Mustafa AK, Sikka G, Gazi SK et al (2011) Hydrogen sulfide as endothelium-derived hyperpolarizing factor sulfhydrates potassium channels. Circ Res 109:1259–1268PubMedCentralPubMedGoogle Scholar
  45. 45.
    Tang G, Yang G, Jiang B, Ju Y, Wu L, Wang R (2013) H2S is an endothelium-derived hyperpolarizing factor. Antioxid Redox Signal 19:1634–1646PubMedGoogle Scholar
  46. 46.
    Guan Q, Zhang Y, Yu C, Liu Y, Gao L, Zhao J (2012) Hydrogen sulfide protects against high-glucose-induced apoptosis in endothelial cells. J Cardiovasc Pharmacol 59:188–193PubMedGoogle Scholar
  47. 47.
    Wang R (2012) Physiological implications of hydrogen sulfide: a whiff exploration that blossomed. Physiol Rev 92:791–896PubMedGoogle Scholar
  48. 48.
    Perna AF, Sepe I, Lanza D et al (2013) Hydrogen sulfide reduces cell adhesion and relevant inflammatory triggering by preventing ADAM17-dependent TNF-alpha activation. J Cell Biochem 114:1536–1548PubMedGoogle Scholar
  49. 49.
    Polhemus DJ, Lefer DJ (2014) Emergence of hydrogen sulfide as an endogenous gaseous signaling molecule in cardiovascular disease. Circ Res 114:730–737PubMedGoogle Scholar
  50. 50.
    Whiteman M, Moore PK (2009) Hydrogen sulfide and the vasculature: a novel vasculoprotective entity and regulator of nitric oxide bioavailability? J Cell Mol Med 13:488–507PubMedGoogle Scholar
  51. 51.
    King AL, Polhemus DJ, Bhushan S et al (2014) Hydrogen sulfide cytoprotective signaling is endothelial nitric oxide synthase-nitric oxide dependent. Proc Natl Acad Sci USA 111:3182–3187PubMedGoogle Scholar
  52. 52.
    Paul BD, Snyder SH (2012) H(2)S signalling through protein sulfhydration and beyond. Nat Rev Mol Cell Biol 13:499–507PubMedGoogle Scholar
  53. 53.
    Mustafa AK, Gadalla MM, Sen N et al (2009) H2S signals through protein S-sulfhydration. Sci Signal 2:ra72PubMedCentralPubMedGoogle Scholar
  54. 54.
    Hourihan JM, Kenna JG, Hayes JD (2013) The gasotransmitter hydrogen sulfide induces nrf2-target genes by inactivating the keap1 ubiquitin ligase substrate adaptor through formation of a disulfide bond between cys-226 and cys-613. Antioxid Redox Signal 19:465–481PubMedGoogle Scholar
  55. 55.
    Li W, Busu C, Circu ML, Aw TY (2012) Glutathione in cerebral microvascular endothelial biology and pathobiology: implications for brain homeostasis. Int J Cell Biol 2012:434971PubMedCentralPubMedGoogle Scholar
  56. 56.
    Okouchi M, Okayama N, Aw TY (2009) Preservation of cellular glutathione status and mitochondrial membrane potential by N-acetylcysteine and insulin sensitizers prevent carbonyl stress-induced human brain endothelial cell apoptosis. Curr Neurovasc Res 6:267–278PubMedCentralPubMedGoogle Scholar
  57. 57.
    Langston W, Chidlow JH Jr, Booth BA et al (2007) Regulation of endothelial glutathione by ICAM-1 governs VEGF-A-mediated eNOS activity and angiogenesis. Free Radic Biol Med 42:720–729PubMedCentralPubMedGoogle Scholar
  58. 58.
    Kugiyama K, Ohgushi M, Motoyama T et al (1998) Intracoronary infusion of reduced glutathione improves endothelial vasomotor response to acetylcholine in human coronary circulation. Circulation 97:2299–2301PubMedGoogle Scholar
  59. 59.
    Dalle-Donne I, Rossi R, Giustarini D, Colombo R, Milzani A (2007) S-glutathionylation in protein redox regulation. Free Radic Biol Med 43:883–898PubMedGoogle Scholar
  60. 60.
    Clavreul N, Adachi T, Pimental DR, Ido Y, Schoneich C, Cohen RA (2006) S-glutathiolation by peroxynitrite of p21ras at cysteine-118 mediates its direct activation and downstream signaling in endothelial cells. FASEB J 20:518–520PubMedGoogle Scholar
  61. 61.
    Li JM, Shah AM (2004) Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology. Am J Physiol Regul Integr Comp Physiol 287:R1014–R1030PubMedGoogle Scholar
  62. 62.
    Du XL, Edelstein D, Rossetti L et al (2000) Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci USA 97:12222–12226PubMedCentralPubMedGoogle Scholar
  63. 63.
    Quintero M, Colombo SL, Godfrey A, Moncada S (2006) Mitochondria as signaling organelles in the vascular endothelium. Proc Natl Acad Sci USA 103:5379–5384PubMedCentralPubMedGoogle Scholar
  64. 64.
    Song P, Zou MH (2012) Regulation of NAD(P)H oxidases by AMPK in cardiovascular systems. Free Radic Biol Med 52:1607–1619PubMedCentralPubMedGoogle Scholar
  65. 65.
    Lassegue B, San Martin A, Griendling KK (2012) Biochemistry, physiology, and pathophysiology of NADPH oxidases in the cardiovascular system. Circ Res 110:1364–1390PubMedCentralPubMedGoogle Scholar
  66. 66.
    Zou MH, Shi C, Cohen RA (2002) Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. J Clin Invest 109:817–826PubMedCentralPubMedGoogle Scholar
  67. 67.
    Landmesser U, Dikalov S, Price SR et al (2003) Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest 111:1201–1209PubMedCentralPubMedGoogle Scholar
  68. 68.
    Thum T, Fraccarollo D, Schultheiss M et al (2007) Endothelial nitric oxide synthase uncoupling impairs endothelial progenitor cell mobilization and function in diabetes. Diabetes 56:666–674PubMedGoogle Scholar
  69. 69.
    Civelek M, Manduchi E, Riley RJ, Stoeckert CJ Jr, Davies PF (2011) Coronary artery endothelial transcriptome in vivo: identification of endoplasmic reticulum stress and enhanced reactive oxygen species by gene connectivity network analysis. Circ Cardiovasc Genet 4:243–252PubMedCentralPubMedGoogle Scholar
  70. 70.
    Malhotra JD, Kaufman RJ (2007) Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid Redox Signal 9:2277–2293PubMedGoogle Scholar
  71. 71.
    Landmesser U, Spiekermann S, Preuss C et al (2007) Angiotensin II induces endothelial xanthine oxidase activation: role for endothelial dysfunction in patients with coronary disease. Arterioscler Thromb Vasc Biol 27:943–948PubMedGoogle Scholar
  72. 72.
    Kou B, Ni J, Vatish M, Singer DR (2008) Xanthine oxidase interaction with vascular endothelial growth factor in human endothelial cell angiogenesis. Microcirculation 15:251–267PubMedGoogle Scholar
  73. 73.
    Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552:335–344PubMedCentralPubMedGoogle Scholar
  74. 74.
    Maranzana E, Barbero G, Falasca AI, Lenaz G, Genova ML (2013) Mitochondrial respiratory supercomplex association limits production of reactive oxygen species from complex I. Antioxid Redox Signal 19:1469–1480PubMedGoogle Scholar
  75. 75.
    Liu Y, Zhao H, Li H, Kalyanaraman B, Nicolosi AC, Gutterman DD (2003) Mitochondrial sources of H2O2 generation play a key role in flow-mediated dilation in human coronary resistance arteries. Circ Res 93:573–580PubMedGoogle Scholar
  76. 76.
    Therade-Matharan S, Laemmel E, Carpentier S et al (2005) Reactive oxygen species production by mitochondria in endothelial cells exposed to reoxygenation after hypoxia and glucose depletion is mediated by ceramide. Am J Physiol Regul Integr Comp Physiol 289:R1756–R1762PubMedGoogle Scholar
  77. 77.
    Xu J, Xie Z, Reece R, Pimental D, Zou MH (2006) Uncoupling of endothelial nitric oxidase synthase by hypochlorous acid: role of NAD(P)H oxidase-derived superoxide and peroxynitrite. Arterioscler Thromb Vasc Biol 26:2688–2695PubMedGoogle Scholar
  78. 78.
    Wang S, Xu J, Song P, Viollet B, Zou MH (2009) In vivo activation of AMP-activated protein kinase attenuates diabetes-enhanced degradation of GTP cyclohydrolase I. Diabetes 58:1893–1901PubMedCentralPubMedGoogle Scholar
  79. 79.
    Xu J, Wu Y, Song P, Zhang M, Wang S, Zou MH (2007) Proteasome-dependent degradation of guanosine 5’-triphosphate cyclohydrolase I causes tetrahydrobiopterin deficiency in diabetes mellitus. Circulation 116:944–953PubMedGoogle Scholar
  80. 80.
    Xu J, Wang S, Zhang M, Wang Q, Asfa S, Zou MH (2012) Tyrosine nitration of PA700 links proteasome activation to endothelial dysfunction in mouse models with cardiovascular risk factors. PLoS ONE 7:e29649PubMedCentralPubMedGoogle Scholar
  81. 81.
    Zhao Y, Wu J, Zhu H, Song P, Zou MH (2013) Peroxynitrite-dependent zinc release and inactivation of guanosine 5’-triphosphate cyclohydrolase 1 instigate its ubiquitination in diabetes. Diabetes 62:4247–4256PubMedGoogle Scholar
  82. 82.
    Hanschmann EM, Godoy JR, Berndt C, Hudemann C, Lillig CH (2013) Thioredoxins, glutaredoxins, and peroxiredoxins-molecular mechanisms and health significance: from cofactors to antioxidants to redox signaling. Antioxid Redox Signal 19:1539–1605PubMedGoogle Scholar
  83. 83.
    Stangherlin A, Reddy AB (2013) Regulation of circadian clocks by redox homeostasis. J Biol Chem 288:26505–26511PubMedGoogle Scholar
  84. 84.
    Ma Q (2013) Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol 53:401–426PubMedGoogle Scholar
  85. 85.
    Oelze M, Kroller-Schon S, Steven S et al (2014) Glutathione peroxidase-1 deficiency potentiates dysregulatory modifications of endothelial nitric oxide synthase and vascular dysfunction in aging. Hypertension 63:390–396PubMedGoogle Scholar
  86. 86.
    Li L, Rose P, Moore PK (2011) Hydrogen sulfide and cell signaling. Annu Rev Pharmacol Toxicol 51:169–187PubMedGoogle Scholar
  87. 87.
    Whiteman M, Armstrong JS, Chu SH et al (2004) The novel neuromodulator hydrogen sulfide: an endogenous peroxynitrite ‘scavenger’? J Neurochem 90:765–768PubMedGoogle Scholar
  88. 88.
    Xie Z, Zhang J, Wu J, Viollet B, Zou MH (2008) Upregulation of mitochondrial uncoupling protein-2 by the AMP-activated protein kinase in endothelial cells attenuates oxidative stress in diabetes. Diabetes 57:3222–3230PubMedCentralPubMedGoogle Scholar
  89. 89.
    Potente M, Urbich C, Sasaki K et al (2005) Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization. J Clin Invest 115:2382–2392PubMedCentralPubMedGoogle Scholar
  90. 90.
    Shen B, Chao L, Chao J (2010) Pivotal role of JNK-dependent FOXO1 activation in downregulation of kallistatin expression by oxidative stress. Am J Physiol Heart Circ Physiol 298:H1048–H1054PubMedCentralPubMedGoogle Scholar
  91. 91.
    Skurk C, Maatz H, Kim HS et al (2004) The Akt-regulated forkhead transcription factor FOXO3a controls endothelial cell viability through modulation of the caspase-8 inhibitor FLIP. J Biol Chem 279:1513–1525PubMedGoogle Scholar
  92. 92.
    Ponugoti B, Dong G, Graves DT (2012) Role of forkhead transcription factors in diabetes-induced oxidative stress. Exp Diabetes Res 2012:939751PubMedCentralPubMedGoogle Scholar
  93. 93.
    Tsuchiya K, Tanaka J, Shuiqing Y et al (2012) FoxOs integrate pleiotropic actions of insulin in vascular endothelium to protect mice from atherosclerosis. Cell Metab 15:372–381PubMedCentralPubMedGoogle Scholar
  94. 94.
    Lee JW, Chen H, Pullikotil P, Quon MJ (2011) Protein kinase A-alpha directly phosphorylates FoxO1 in vascular endothelial cells to regulate expression of vascular cellular adhesion molecule-1 mRNA. J Biol Chem 286:6423–6432PubMedCentralPubMedGoogle Scholar
  95. 95.
    Mortuza R, Chen S, Feng B, Sen S, Chakrabarti S (2013) High glucose induced alteration of SIRTs in endothelial cells causes rapid aging in a p300 and FOXO regulated pathway. PLoS ONE 8:e54514PubMedCentralPubMedGoogle Scholar
  96. 96.
    Olmos Y, Valle I, Borniquel S et al (2009) Mutual dependence of Foxo3a and PGC-1alpha in the induction of oxidative stress genes. J Biol Chem 284:14476–14484PubMedCentralPubMedGoogle Scholar
  97. 97.
    Tanaka J, Qiang L, Banks AS et al (2009) Foxo1 links hyperglycemia to LDL oxidation and endothelial nitric oxide synthase dysfunction in vascular endothelial cells. Diabetes 58:2344–2354PubMedCentralPubMedGoogle Scholar
  98. 98.
    Daly C, Wong V, Burova E et al (2004) Angiopoietin-1 modulates endothelial cell function and gene expression via the transcription factor FKHR (FOXO1). Genes Dev 18:1060–1071PubMedCentralPubMedGoogle Scholar
  99. 99.
    Kim HS, Skurk C, Maatz H et al (2005) Akt/FOXO3a signaling modulates the endothelial stress response through regulation of heat shock protein 70 expression. FASEB J 19:1042–1044PubMedGoogle Scholar
  100. 100.
    Kensler TW, Wakabayashi N, Biswal S (2007) Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol 47:89–116PubMedGoogle Scholar
  101. 101.
    Cheng X, Siow RC, Mann GE (2011) Impaired redox signaling and antioxidant gene expression in endothelial cells in diabetes: a role for mitochondria and the nuclear factor-E2-related factor 2-Kelch-like ECH-associated protein 1 defense pathway. Antioxid Redox Signal 14:469–487PubMedGoogle Scholar
  102. 102.
    Kobayashi A, Kang MI, Okawa H et al (2004) Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol 24:7130–7139PubMedCentralPubMedGoogle Scholar
  103. 103.
    Zhang DD, Lo SC, Cross JV, Templeton DJ, Hannink M (2004) Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol Cell Biol 24:10941–10953PubMedCentralPubMedGoogle Scholar
  104. 104.
    Chen XL, Dodd G, Thomas S et al (2006) Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression. Am J Physiol Heart Circ Physiol 290:H1862–H1870PubMedGoogle Scholar
  105. 105.
    Hsieh HJ, Cheng CC, Wu ST, Chiu JJ, Wung BS, Wang DL (1998) Increase of reactive oxygen species (ROS) in endothelial cells by shear flow and involvement of ROS in shear-induced c-fos expression. J Cell Physiol 175:156–162PubMedGoogle Scholar
  106. 106.
    Hsieh CY, Hsiao HY, Wu WY et al (2009) Regulation of shear-induced nuclear translocation of the Nrf2 transcription factor in endothelial cells. J Biomed Sci 16:12PubMedCentralPubMedGoogle Scholar
  107. 107.
    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:E3910–E3918PubMedCentralPubMedGoogle Scholar
  108. 108.
    Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92:5510–5514PubMedCentralPubMedGoogle Scholar
  109. 109.
    Jiang BH, Rue E, Wang GL, Roe R, Semenza GL (1996) Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J Biol Chem 271:17771–17778PubMedGoogle Scholar
  110. 110.
    Palmer LA, Gaston B, Johns RA (2000) Normoxic stabilization of hypoxia-inducible factor-1 expression and activity: redox-dependent effect of nitrogen oxides. Mol Pharmacol 58:1197–1203PubMedGoogle Scholar
  111. 111.
    Loboda A, Stachurska A, Florczyk U et al (2009) HIF-1 induction attenuates Nrf2-dependent IL-8 expression in human endothelial cells. Antioxid Redox Signal 11:1501–1517PubMedGoogle Scholar
  112. 112.
    Chung HS, Wang SB, Venkatraman V, Murray CI, Van Eyk JE (2013) Cysteine oxidative posttranslational modifications: emerging regulation in the cardiovascular system. Circ Res 112:382–392PubMedGoogle Scholar
  113. 113.
    Cremers CM, Jakob U (2013) Oxidant sensing by reversible disulfide bond formation. J Biol Chem 288:26489–26496PubMedGoogle Scholar
  114. 114.
    Connor KM, Subbaram S, Regan KJ et al (2005) Mitochondrial H2O2 regulates the angiogenic phenotype via PTEN oxidation. J Biol Chem 280:16916–16924PubMedGoogle Scholar
  115. 115.
    Lima B, Forrester MT, Hess DT, Stamler JS (2010) S-nitrosylation in cardiovascular signaling. Circ Res 106:633–646PubMedCentralPubMedGoogle Scholar
  116. 116.
    Ravi K, Brennan LA, Levic S, Ross PA, Black SM (2004) S-nitrosylation of endothelial nitric oxide synthase is associated with monomerization and decreased enzyme activity. Proc Natl Acad Sci USA 101:2619–2624PubMedCentralPubMedGoogle Scholar
  117. 117.
    Hill BG, Bhatnagar A (2007) Role of glutathiolation in preservation, restoration and regulation of protein function. IUBMB Life 59:21–26PubMedGoogle Scholar
  118. 118.
    Mieyal JJ, Gallogly MM, Qanungo S, Sabens EA, Shelton MD (2008) Molecular mechanisms and clinical implications of reversible protein S-glutathionylation. Antioxid Redox Signal 10:1941–1988PubMedCentralPubMedGoogle Scholar
  119. 119.
    Grek CL, Zhang J, Manevich Y, Townsend DM, Tew KD (2013) Causes and consequences of cysteine S-glutathionylation. J Biol Chem 288:26497–26504PubMedGoogle Scholar
  120. 120.
    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 285:33154–33164PubMedCentralPubMedGoogle Scholar
  121. 121.
    Evangelista AM, Thompson MD, Weisbrod RM et al (2012) Redox regulation of SERCA2 is required for vascular endothelial growth factor-induced signaling and endothelial cell migration. Antioxid Redox Signal 17:1099–1108PubMedCentralPubMedGoogle Scholar
  122. 122.
    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 53:2327–2334PubMedGoogle Scholar
  123. 123.
    Clavreul N, Bachschmid MM, Hou X et al (2006) S-glutathiolation of p21ras by peroxynitrite mediates endothelial insulin resistance caused by oxidized low-density lipoprotein. Arterioscler Thromb Vasc Biol 26:2454–2461PubMedGoogle Scholar
  124. 124.
    Chen CA, Wang TY, Varadharaj S et al (2010) S-glutathionylation uncouples eNOS and regulates its cellular and vascular function. Nature 468:1115–1118PubMedCentralPubMedGoogle Scholar
  125. 125.
    Wang Y, Yang J, Yi J (2012) Redox sensing by proteins: oxidative modifications on cysteines and the consequent events. Antioxid Redox Signal 16:649–657PubMedGoogle Scholar
  126. 126.
    Wang K, Zhang T, Dong Q, Nice EC, Huang C, Wei Y (2013) Redox homeostasis: the linchpin in stem cell self-renewal and differentiation. Cell Death Dis 4:e537PubMedCentralPubMedGoogle Scholar
  127. 127.
    Zhang J, Xie Z, Dong Y, Wang S, Liu C, Zou MH (2008) Identification of nitric oxide as an endogenous activator of the AMP-activated protein kinase in vascular endothelial cells. J Biol Chem 283:27452–27461PubMedCentralPubMedGoogle Scholar
  128. 128.
    Han Y, Wang Q, Song P, Zhu Y, Zou MH (2010) Redox regulation of the AMP-activated protein kinase. PLoS ONE 5:e15420PubMedCentralPubMedGoogle Scholar
  129. 129.
    Song P, Wang S, He C, Liang B, Viollet B, Zou MH (2011) AMPKalpha2 deletion exacerbates neointima formation by upregulating Skp2 in vascular smooth muscle cells. Circ Res 109:1230–1239PubMedCentralPubMedGoogle Scholar
  130. 130.
    Song P, Zhou Y, Coughlan KA et al (2013) Adenosine monophosphate-activated protein kinase-alpha2 deficiency promotes vascular smooth muscle cell migration via S-phase kinase-associated protein 2 upregulation and E-cadherin downregulation. Arterioscler Thromb Vasc Biol 33:2800–2809PubMedCentralPubMedGoogle Scholar
  131. 131.
    Wang S, Song P, Zou MH (2012) AMP-activated protein kinase, stress responses and cardiovascular diseases. Clin Sci (Lond) 122:555–573Google Scholar
  132. 132.
    Zou MH, Hou XY, Shi CM, Nagata D, Walsh K, Cohen RA (2002) Modulation by peroxynitrite of Akt- and AMP-activated kinase-dependent Ser1179 phosphorylation of endothelial nitric oxide synthase. J Biol Chem 277:32552–32557PubMedGoogle Scholar
  133. 133.
    Song P, Wu Y, Xu J et al (2007) Reactive nitrogen species induced by hyperglycemia suppresses Akt signaling and triggers apoptosis by upregulating phosphatase PTEN (phosphatase and tensin homologue deleted on chromosome 10) in an LKB1-dependent manner. Circulation 116:1585–1595PubMedGoogle Scholar
  134. 134.
    Song P, Xie Z, Wu Y, Xu J, Dong Y, Zou MH (2008) Protein kinase Czeta-dependent LKB1 serine 428 phosphorylation increases LKB1 nucleus export and apoptosis in endothelial cells. J Biol Chem 283:12446–12455PubMedCentralPubMedGoogle Scholar
  135. 135.
    Wang Q, Zhang M, Ding Y et al (2014) Activation of NAD(P)H oxidase by tryptophan-derived 3-hydroxykynurenine accelerates endothelial apoptosis and dysfunction in vivo. Circ Res 114:480–492PubMedCentralPubMedGoogle Scholar
  136. 136.
    Ido Y, Carling D, Ruderman N (2002) Hyperglycemia-induced apoptosis in human umbilical vein endothelial cells: inhibition by the AMP-activated protein kinase activation. Diabetes 51:159–167PubMedGoogle Scholar
  137. 137.
    Zhang M, Dong Y, Xu J et al (2008) Thromboxane receptor activates the AMP-activated protein kinase in vascular smooth muscle cells via hydrogen peroxide. Circ Res 102:328–337PubMedCentralPubMedGoogle Scholar
  138. 138.
    Zou MH, Kirkpatrick SS, Davis BJ et al (2004) Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo. Role of mitochondrial reactive nitrogen species. J Biol Chem 279:43940–43951PubMedGoogle Scholar
  139. 139.
    Zou MH, Hou XY, Shi CM et al (2003) Activation of 5’-AMP-activated kinase is mediated through c-Src and phosphoinositide 3-kinase activity during hypoxia-reoxygenation of bovine aortic endothelial cells. Role of peroxynitrite. J Biol Chem 278:34003–34010PubMedGoogle Scholar
  140. 140.
    Choi HC, Song P, Xie Z et al (2008) Reactive nitrogen species is required for the activation of the AMP-activated protein kinase by statin in vivo. J Biol Chem 283:20186–20197PubMedCentralPubMedGoogle Scholar
  141. 141.
    Liu C, Liang B, Wang Q, Wu J, Zou MH (2010) Activation of AMP-activated protein kinase alpha1 alleviates endothelial cell apoptosis by increasing the expression of anti-apoptotic proteins Bcl-2 and survivin. J Biol Chem 285:15346–15355PubMedCentralPubMedGoogle Scholar
  142. 142.
    Colombo SL, Moncada S (2009) AMPKalpha1 regulates the antioxidant status of vascular endothelial cells. Biochem J 421:163–169PubMedGoogle Scholar
  143. 143.
    Bhatt MP, Lim YC, Kim YM, Ha KS (2013) C-peptide activates AMPKalpha and prevents ROS-mediated mitochondrial fission and endothelial apoptosis in diabetes. Diabetes 62:3851–3862PubMedGoogle Scholar
  144. 144.
    Cifarelli V, Lee S, Kim DH et al (2012) FOXO1 mediates the autocrine effect of endothelin-1 on endothelial cell survival. Mol Endocrinol 26:1213–1224PubMedCentralPubMedGoogle Scholar
  145. 145.
    Burhans WC, Heintz NH (2009) The cell cycle is a redox cycle: linking phase-specific targets to cell fate. Free Radic Biol Med 47:1282–1293PubMedGoogle Scholar
  146. 146.
    Sarsour EH, Kumar MG, Chaudhuri L, Kalen AL, Goswami PC (2009) Redox control of the cell cycle in health and disease. Antioxid Redox Signal 11:2985–3011PubMedCentralPubMedGoogle Scholar
  147. 147.
    Menon SG, Goswami PC (2007) A redox cycle within the cell cycle: ring in the old with the new. Oncogene 26:1101–1109PubMedGoogle Scholar
  148. 148.
    Latella L, Sacco A, Pajalunga D et al (2001) Reconstitution of cyclin D1-associated kinase activity drives terminally differentiated cells into the cell cycle. Mol Cell Biol 21:5631–5643PubMedCentralPubMedGoogle Scholar
  149. 149.
    Ushio-Fukai M (2006) Redox signaling in angiogenesis: role of NADPH oxidase. Cardiovasc Res 71:226–235PubMedGoogle Scholar
  150. 150.
    Wang Y, Zang QS, Liu Z et al (2011) Regulation of VEGF-induced endothelial cell migration by mitochondrial reactive oxygen species. Am J Physiol Cell Physiol 301:C695–C704PubMedCentralPubMedGoogle Scholar
  151. 151.
    Ashton AW, Ware JA (2004) Thromboxane A2 receptor signaling inhibits vascular endothelial growth factor-induced endothelial cell differentiation and migration. Circ Res 95:372–379PubMedGoogle Scholar
  152. 152.
    Song P, Zhang M, Wang S, Xu J, Choi HC, Zou MH (2009) Thromboxane A2 receptor activates a rho-associated kinase/LKB1/PTEN pathway to attenuate endothelium insulin signaling. J Biol Chem 284:17120–17128PubMedCentralPubMedGoogle Scholar
  153. 153.
    Xu MJ, Song P, Shirwany N et al (2011) Impaired expression of uncoupling protein 2 causes defective postischemic angiogenesis in mice deficient in AMP-activated protein kinase alpha subunits. Arterioscler Thromb Vasc Biol 31:1757–1765PubMedCentralPubMedGoogle Scholar
  154. 154.
    Zippel N, Malik RA, Fromel T et al (2013) Transforming growth factor-beta-activated kinase 1 regulates angiogenesis via AMP-activated protein kinase-alpha1 and redox balance in endothelial cells. Arterioscler Thromb Vasc Biol 33:2792–2799PubMedGoogle Scholar
  155. 155.
    Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421:499–506PubMedGoogle Scholar
  156. 156.
    Okuno Y, Nakamura-Ishizu A, Otsu K, Suda T, Kubota Y (2012) Pathological neoangiogenesis depends on oxidative stress regulation by ATM. Nat Med 18:1208–1216PubMedGoogle Scholar
  157. 157.
    Jansen F, Yang X, Hoelscher M et al (2013) Endothelial microparticle-mediated transfer of MicroRna-126 promotes vascular endothelial cell repair via SPRED1 and is abrogated in glucose-damaged endothelial microparticles. Circulation 128:2026–2038PubMedGoogle Scholar
  158. 158.
    Papapetropoulos A, Pyriochou A, Altaany Z et al (2009) Hydrogen sulfide is an endogenous stimulator of angiogenesis. Proc Natl Acad Sci USA 106:21972–21977PubMedCentralPubMedGoogle Scholar
  159. 159.
    Cacicedo JM, Yagihashi N, Keaney JF Jr, Ruderman NB, Ido Y (2004) AMPK inhibits fatty acid-induced increases in NF-kappaB transactivation in cultured human umbilical vein endothelial cells. Biochem Biophys Res Commun 324:1204–1209PubMedGoogle Scholar
  160. 160.
    Hattori Y, Nakano Y, Hattori S, Tomizawa A, Inukai K, Kasai K (2008) High molecular weight adiponectin activates AMPK and suppresses cytokine-induced NF-kappaB activation in vascular endothelial cells. FEBS Lett 582:1719–1724PubMedGoogle Scholar
  161. 161.
    Bess E, Fisslthaler B, Fromel T, Fleming I (2011) Nitric oxide-induced activation of the AMP-activated protein kinase alpha2 subunit attenuates IkappaB kinase activity and inflammatory responses in endothelial cells. PLoS ONE 6:e20848PubMedCentralPubMedGoogle Scholar
  162. 162.
    Delhase M, Hayakawa M, Chen Y, Karin M (1999) Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation. Science 284:309–313PubMedGoogle Scholar
  163. 163.
    Seldon MP, Silva G, Pejanovic N et al (2007) Heme oxygenase-1 inhibits the expression of adhesion molecules associated with endothelial cell activation via inhibition of NF-kappaB RelA phosphorylation at serine 276. J Immunol 179:7840–7851PubMedGoogle Scholar
  164. 164.
    Xiao H, Lu M, Lin TY et al (2013) Sterol regulatory element binding protein 2 activation of NLRP3 inflammasome in endothelium mediates hemodynamic-induced atherosclerosis susceptibility. Circulation 128:632–642PubMedCentralPubMedGoogle Scholar
  165. 165.
    Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J (2010) Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol 11:136–140PubMedGoogle Scholar
  166. 166.
    Dostert C, Petrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J (2008) Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320:674–677PubMedCentralPubMedGoogle Scholar
  167. 167.
    Pan LL, Liu XH, Gong QH, Wu D, Zhu YZ (2011) Hydrogen sulfide attenuated tumor necrosis factor-alpha-induced inflammatory signaling and dysfunction in vascular endothelial cells. PLoS ONE 6:e19766PubMedCentralPubMedGoogle Scholar
  168. 168.
    van der Loo B, Schildknecht S, Zee R, Bachschmid MM (2009) Signalling processes in endothelial ageing in relation to chronic oxidative stress and their potential therapeutic implications in humans. Exp Physiol 94:305–310PubMedCentralPubMedGoogle Scholar
  169. 169.
    Burger D, Kwart DG, Montezano AC et al (2012) Microparticles induce cell cycle arrest through redox-sensitive processes in endothelial cells: implications in vascular senescence. J Am Heart Assoc 1:e001842PubMedCentralPubMedGoogle Scholar
  170. 170.
    Levenberg S, Golub JS, Amit M, Itskovitz-Eldor J, Langer R (2002) Endothelial cells derived from human embryonic stem cells. Proc Natl Acad Sci USA 99:4391–4396PubMedCentralPubMedGoogle Scholar
  171. 171.
    Wang ZZ, Au P, Chen T et al (2007) Endothelial cells derived from human embryonic stem cells form durable blood vessels in vivo. Nat Biotechnol 25:317–318PubMedGoogle Scholar
  172. 172.
    Samuel R, Daheron L, Liao S et al (2013) Generation of functionally competent and durable engineered blood vessels from human induced pluripotent stem cells. Proc Natl Acad Sci USA 110:12774–12779PubMedCentralPubMedGoogle Scholar
  173. 173.
    Margariti A, Winkler B, Karamariti E et al (2012) Direct reprogramming of fibroblasts into endothelial cells capable of angiogenesis and reendothelialization in tissue-engineered vessels. Proc Natl Acad Sci USA 109:13793–13798PubMedCentralPubMedGoogle Scholar
  174. 174.
    Junker JP, Lonnqvist S, Rakar J, Karlsson LK, Grenegard M, Kratz G (2013) Differentiation of human dermal fibroblasts towards endothelial cells. Differentiation 85:67–77PubMedGoogle Scholar
  175. 175.
    Oswald J, Boxberger S, Jorgensen B et al (2004) Mesenchymal stem cells can be differentiated into endothelial cells in vitro. Stem Cells 22:377–384PubMedGoogle Scholar
  176. 176.
    Zhang P, Moudgill N, Hager E et al (2011) Endothelial differentiation of adipose-derived stem cells from elderly patients with cardiovascular disease. Stem Cells Dev 20:977–988PubMedCentralPubMedGoogle Scholar
  177. 177.
    Fischer LJ, McIlhenny S, Tulenko T et al (2009) Endothelial differentiation of adipose-derived stem cells: effects of endothelial cell growth supplement and shear force. J Surg Res 152:157–166PubMedCentralPubMedGoogle Scholar
  178. 178.
    Planat-Benard V, Silvestre JS, Cousin B et al (2004) Plasticity of human adipose lineage cells toward endothelial cells: physiological and therapeutic perspectives. Circulation 109:656–663PubMedGoogle Scholar
  179. 179.
    Soda Y, Marumoto T, Friedmann-Morvinski D et al (2011) Transdifferentiation of glioblastoma cells into vascular endothelial cells. Proc Natl Acad Sci USA 108:4274–4280PubMedCentralPubMedGoogle Scholar
  180. 180.
    Zeng L, Xiao Q, Margariti A et al (2006) HDAC3 is crucial in shear- and VEGF-induced stem cell differentiation toward endothelial cells. J Cell Biol 174:1059–1069PubMedCentralPubMedGoogle Scholar
  181. 181.
    Yamamoto K, Sokabe T, Watabe T et al (2005) Fluid shear stress induces differentiation of Flk-1-positive embryonic stem cells into vascular endothelial cells in vitro. Am J Physiol Heart Circ Physiol 288:H1915–H1924PubMedGoogle Scholar
  182. 182.
    Zhang C, Zeng L, Emanueli C, Xu Q (2013) Blood flow and stem cells in vascular disease. Cardiovasc Res 99:251–259PubMedGoogle Scholar
  183. 183.
    Marcelo KL, Goldie LC, Hirschi KK (2013) Regulation of endothelial cell differentiation and specification. Circ Res 112:1272–1287PubMedCentralPubMedGoogle Scholar
  184. 184.
    Myers CT, Krieg PA (2013) BMP-mediated specification of the erythroid lineage suppresses endothelial development in blood island precursors. Blood 122:3929–3939PubMedGoogle Scholar
  185. 185.
    Wang S, Dale GL, Song P, Viollet B, Zou MH (2010) AMPKalpha1 deletion shortens erythrocyte life span in mice: role of oxidative stress. J Biol Chem 285:19976–19985PubMedCentralPubMedGoogle Scholar
  186. 186.
    Arciniegas E, Sutton AB, Allen TD, Schor AM (1992) Transforming growth factor beta 1 promotes the differentiation of endothelial cells into smooth muscle-like cells in vitro. J Cell Sci 103(Pt 2):521–529PubMedGoogle Scholar
  187. 187.
    DeRuiter MC, Poelmann RE, VanMunsteren JC, Mironov V, Markwald RR, Gittenberger-de Groot AC (1997) Embryonic endothelial cells transdifferentiate into mesenchymal cells expressing smooth muscle actins in vivo and in vitro. Circ Res 80:444–451PubMedGoogle Scholar
  188. 188.
    Banerji S, Ni J, Wang SX et al (1999) LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol 144:789–801PubMedCentralPubMedGoogle Scholar
  189. 189.
    Hong YK, Harvey N, Noh YH et al (2002) Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate. Dev Dyn 225:351–357PubMedGoogle Scholar
  190. 190.
    Adams RH, Alitalo K (2007) Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 8:464–478PubMedGoogle Scholar
  191. 191.
    Cooley LS, Handsley MM, Zhou Z et al (2010) Reversible transdifferentiation of blood vascular endothelial cells to a lymphatic-like phenotype in vitro. J Cell Sci 123:3808–3816PubMedGoogle Scholar
  192. 192.
    Medici D, Shore EM, Lounev VY, Kaplan FS, Kalluri R, Olsen BR (2010) Conversion of vascular endothelial cells into multipotent stem-like cells. Nat Med 16:1400–1406PubMedCentralPubMedGoogle Scholar
  193. 193.
    Goumans MJ, van Zonneveld AJ, ten Dijke P (2008) Transforming growth factor beta-induced endothelial-to-mesenchymal transition: a switch to cardiac fibrosis? Trends Cardiovasc Med 18:293–298PubMedGoogle Scholar
  194. 194.
    Gupta RK, Mepani RJ, Kleiner S et al (2012) Zfp423 expression identifies committed preadipocytes and localizes to adipose endothelial and perivascular cells. Cell Metab 15:230–239PubMedCentralPubMedGoogle Scholar
  195. 195.
    Sena CM, Pereira AM, Seica R (2013) Endothelial dysfunction—a major mediator of diabetic vascular disease. Biochim Biophys Acta 1832:2216–2231PubMedGoogle Scholar
  196. 196.
    Hopkins PN (2013) Molecular biology of atherosclerosis. Physiol Rev 93:1317–1542PubMedGoogle Scholar
  197. 197.
    Sukumar P, Viswambharan H, Imrie H et al (2013) Nox2 NADPH oxidase has a critical role in insulin resistance-related endothelial cell dysfunction. Diabetes 62:2130–2134PubMedCentralPubMedGoogle Scholar
  198. 198.
    Gray SP, Di Marco E, Okabe J et al (2013) NADPH oxidase 1 plays a key role in diabetes mellitus-accelerated atherosclerosis. Circulation 127:1888–1902PubMedGoogle Scholar
  199. 199.
    Wang S, Zhang M, Liang B et al (2010) AMPKalpha2 deletion causes aberrant expression and activation of NAD(P)H oxidase and consequent endothelial dysfunction in vivo: role of 26S proteasomes. Circ Res 106:1117–1128PubMedCentralPubMedGoogle Scholar
  200. 200.
    Dong Y, Zhang M, Wang S et al (2010) Activation of AMP-activated protein kinase inhibits oxidized LDL-triggered endoplasmic reticulum stress in vivo. Diabetes 59:1386–1396PubMedCentralPubMedGoogle Scholar
  201. 201.
    Zhang M, Song P, Xu J, Zou MH (2011) Activation of NAD(P)H oxidases by thromboxane A2 receptor uncouples endothelial nitric oxide synthase. Arterioscler Thromb Vasc Biol 31:125–132PubMedCentralPubMedGoogle Scholar
  202. 202.
    Mani S, Untereiner A, Wu L, Wang R (2014) Hydrogen sulfide and the pathogenesis of atherosclerosis. Antioxid Redox Signal 20:805–817PubMedGoogle Scholar
  203. 203.
    Wang Y, Zhao X, Jin H et al (2009) Role of hydrogen sulfide in the development of atherosclerotic lesions in apolipoprotein E knockout mice. Arterioscler Thromb Vasc Biol 29:173–179PubMedGoogle Scholar
  204. 204.
    Wang S, Xu J, Song P et al (2008) Acute inhibition of guanosine triphosphate cyclohydrolase 1 uncouples endothelial nitric oxide synthase and elevates blood pressure. Hypertension 52:484–490PubMedCentralPubMedGoogle Scholar
  205. 205.
    Xu J, Wang S, Wu Y, Song P, Zou MH (2009) Tyrosine nitration of PA700 activates the 26S proteasome to induce endothelial dysfunction in mice with angiotensin II-induced hypertension. Hypertension 54:625–632PubMedCentralPubMedGoogle Scholar
  206. 206.
    Paravicini TM, Touyz RM (2008) NADPH oxidases, reactive oxygen species, and hypertension: clinical implications and therapeutic possibilities. Diabetes Care 31(Suppl 2):S170–S180PubMedGoogle Scholar
  207. 207.
    Kris-Etherton PM, Harris WS, Appel LJ, American Heart Association, Nutrition C (2002) Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 106:2747–2757PubMedGoogle Scholar
  208. 208.
    Wu Y, Zhang C, Dong Y et al (2012) Activation of the AMP-activated protein kinase by eicosapentaenoic acid (EPA, 20:5 n-3) improves endothelial function in vivo. PLoS ONE 7:e35508PubMedCentralPubMedGoogle Scholar
  209. 209.
    Zhao W, Zhang J, Lu Y, Wang R (2001) The vasorelaxant effect of H(2)S as a novel endogenous gaseous K(ATP) channel opener. EMBO J 20:6008–6016PubMedCentralPubMedGoogle Scholar
  210. 210.
    Yanfei W, Lin S, Junbao D, Chaoshu T (2006) Impact of l-arginine on hydrogen sulfide/cystathionine-gamma-lyase pathway in rats with high blood flow-induced pulmonary hypertension. Biochem Biophys Res Commun 345:851–857PubMedGoogle Scholar
  211. 211.
    Yan H, Du J, Tang C (2004) The possible role of hydrogen sulfide on the pathogenesis of spontaneous hypertension in rats. Biochem Biophys Res Commun 313:22–27PubMedGoogle Scholar
  212. 212.
    Peter EA, Shen X, Shah SH et al (2013) Plasma free H2S levels are elevated in patients with cardiovascular disease. J Am Heart Assoc 2:e000387PubMedCentralPubMedGoogle Scholar
  213. 213.
    Albini A, Tosetti F, Li VW, Noonan DM, Li WW (2012) Cancer prevention by targeting angiogenesis. Nat Rev Clin Oncol 9:498–509PubMedGoogle Scholar
  214. 214.
    Reymond N, d’Agua BB, Ridley AJ (2013) Crossing the endothelial barrier during metastasis. Nat Rev Cancer 13:858–870PubMedGoogle Scholar
  215. 215.
    Xia C, Meng Q, Liu LZ, Rojanasakul Y, Wang XR, Jiang BH (2007) Reactive oxygen species regulate angiogenesis and tumor growth through vascular endothelial growth factor. Cancer Res 67:10823–10830PubMedGoogle Scholar
  216. 216.
    Parri M, Chiarugi P (2013) Redox molecular machines involved in tumor progression. Antioxid Redox Signal 19:1828–1845PubMedGoogle Scholar
  217. 217.
    West XZ, Malinin NL, Merkulova AA et al (2010) Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands. Nature 467:972–976PubMedCentralPubMedGoogle Scholar
  218. 218.
    Daquinag AC, Zhang Y, Kolonin MG (2011) Vascular targeting of adipose tissue as an anti-obesity approach. Trends Pharmacol Sci 32:300–307PubMedGoogle Scholar
  219. 219.
    Cao Y (2010) Adipose tissue angiogenesis as a therapeutic target for obesity and metabolic diseases. Nat Rev Drug Discov 9:107–115PubMedGoogle Scholar
  220. 220.
    Kim CS, Park HS, Kawada T et al (2006) Circulating levels of MCP-1 and IL-8 are elevated in human obese subjects and associated with obesity-related parameters. Int J Obes (Lond) 30:1347–1355Google Scholar
  221. 221.
    Kim SJ, Moon GJ, Cho YH et al (2012) Circulating mesenchymal stem cells microparticles in patients with cerebrovascular disease. PLoS ONE 7:e37036PubMedCentralPubMedGoogle Scholar
  222. 222.
    Roufosse CA, Direkze NC, Otto WR, Wright NA (2004) Circulating mesenchymal stem cells. Int J Biochem Cell Biol 36:585–597PubMedGoogle Scholar
  223. 223.
    Cao Y (2007) Angiogenesis modulates adipogenesis and obesity. J Clin Invest 117:2362–2368PubMedCentralPubMedGoogle Scholar
  224. 224.
    Villaret A, Galitzky J, Decaunes P et al (2010) Adipose tissue endothelial cells from obese human subjects: differences among depots in angiogenic, metabolic, and inflammatory gene expression and cellular senescence. Diabetes 59:2755–2763PubMedCentralPubMedGoogle Scholar
  225. 225.
    Gealekman O, Guseva N, Hartigan C et al (2011) Depot-specific differences and insufficient subcutaneous adipose tissue angiogenesis in human obesity. Circulation 123:186–194PubMedCentralPubMedGoogle Scholar
  226. 226.
    Brakenhielm E, Cao R, Gao B et al (2004) Angiogenesis inhibitor, TNP-470, prevents diet-induced and genetic obesity in mice. Circ Res 94:1579–1588PubMedGoogle Scholar
  227. 227.
    Rupnick MA, Panigrahy D, Zhang CY et al (2002) Adipose tissue mass can be regulated through the vasculature. Proc Natl Acad Sci USA 99:10730–10735PubMedCentralPubMedGoogle Scholar
  228. 228.
    Tam J, Duda DG, Perentes JY, Quadri RS, Fukumura D, Jain RK (2009) Blockade of VEGFR2 and not VEGFR1 can limit diet-induced fat tissue expansion: role of local versus bone marrow-derived endothelial cells. PLoS ONE 4:e4974PubMedCentralPubMedGoogle Scholar
  229. 229.
    Lim S, Honek J, Xue Y et al (2012) Cold-induced activation of brown adipose tissue and adipose angiogenesis in mice. Nat Protoc 7:606–615PubMedGoogle Scholar
  230. 230.
    Xue Y, Lim S, Brakenhielm E, Cao Y (2010) Adipose angiogenesis: quantitative methods to study microvessel growth, regression and remodeling in vivo. Nat Protoc 5:912–920PubMedGoogle Scholar
  231. 231.
    Bartelt A, Heeren J (2014) Adipose tissue browning and metabolic health. Nat Rev Endocrinol 10:24–36PubMedGoogle Scholar
  232. 232.
    Cheng X, Chapple SJ, Patel B et al (2013) Gestational diabetes mellitus impairs Nrf2-mediated adaptive antioxidant defenses and redox signaling in fetal endothelial cells in utero. Diabetes 62:4088–4097PubMedGoogle Scholar
  233. 233.
    Sobngwi E, Boudou P, Mauvais-Jarvis F et al (2003) Effect of a diabetic environment in utero on predisposition to type 2 diabetes. Lancet 361:1861–1865PubMedGoogle Scholar
  234. 234.
    Duplain H, Burcelin R, Sartori C et al (2001) Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase. Circulation 104:342–345PubMedGoogle Scholar
  235. 235.
    Le Gouill E, Jimenez M, Binnert C et al (2007) Endothelial nitric oxide synthase (eNOS) knockout mice have defective mitochondrial beta-oxidation. Diabetes 56:2690–2696PubMedGoogle Scholar
  236. 236.
    Sansbury BE, Cummins TD, Tang Y et al (2012) Overexpression of endothelial nitric oxide synthase prevents diet-induced obesity and regulates adipocyte phenotype. Circ Res 111:1176–1189PubMedCentralPubMedGoogle Scholar
  237. 237.
    Wang H, Wang AX, Aylor K, Barrett EJ (2013) Nitric oxide directly promotes vascular endothelial insulin transport. Diabetes 62:4030–4042PubMedGoogle Scholar
  238. 238.
    Nelson ER, Wardell SE, Jasper JS et al (2013) 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Science 342:1094–1098PubMedGoogle Scholar
  239. 239.
    Lijnen HR (2008) Angiogenesis and obesity. Cardiovasc Res 78:286–293PubMedGoogle Scholar
  240. 240.
    Feldmann HM, Golozoubova V, Cannon B, Nedergaard J (2009) UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab 9:203–209PubMedGoogle Scholar
  241. 241.
    Xue Y, Petrovic N, Cao R et al (2009) Hypoxia-independent angiogenesis in adipose tissues during cold acclimation. Cell Metab 9:99–109PubMedGoogle Scholar
  242. 242.
    Wang J, Liu R, Wang F et al (2013) Ablation of LGR4 promotes energy expenditure by driving white-to-brown fat switch. Nat Cell Biol 15:1455–1463PubMedGoogle Scholar
  243. 243.
    Baker PR, Lin Y, Schopfer FJ et al (2005) Fatty acid transduction of nitric oxide signaling: multiple nitrated unsaturated fatty acid derivatives exist in human blood and urine and serve as endogenous peroxisome proliferator-activated receptor ligands. J Biol Chem 280:42464–42475PubMedCentralPubMedGoogle Scholar
  244. 244.
    Lima ES, Bonini MG, Augusto O, Barbeiro HV, Souza HP, Abdalla DS (2005) Nitrated lipids decompose to nitric oxide and lipid radicals and cause vasorelaxation. Free Radic Biol Med 39:532–539PubMedGoogle Scholar
  245. 245.
    Trostchansky A, Bonilla L, Gonzalez-Perilli L, Rubbo H (2013) Nitro-fatty acids: formation, redox signaling, and therapeutic potential. Antioxid Redox Signal 19:1257–1265PubMedGoogle Scholar
  246. 246.
    Wu Y, Dong Y, Song P, Zou MH (2012) Activation of the AMP-activated protein kinase (AMPK) by nitrated lipids in endothelial cells. PLoS ONE 7:e31056PubMedCentralPubMedGoogle Scholar
  247. 247.
    Streeter E, Ng HH, Hart JL (2013) Hydrogen sulfide as a vasculoprotective factor. Med Gas Res 3:9PubMedCentralPubMedGoogle Scholar
  248. 248.
    Kashfi K (2014) Anti-cancer activity of new designer hydrogen sulfide-donating hybrids. Antioxid Redox Signal 20:831–846PubMedGoogle Scholar
  249. 249.
    Predmore BL, Lefer DJ (2010) Development of hydrogen sulfide-based therapeutics for cardiovascular disease. J Cardiovasc Transl Res 3:487–498PubMedGoogle Scholar
  250. 250.
    Benavides GA, Squadrito GL, Mills RW et al (2007) Hydrogen sulfide mediates the vasoactivity of garlic. Proc Natl Acad Sci USA 104:17977–17982PubMedCentralPubMedGoogle Scholar
  251. 251.
    Ried K, Frank OR, Stocks NP (2013) Aged garlic extract reduces blood pressure in hypertensives: a dose-response trial. Eur J Clin Nutr 67:64–70PubMedCentralPubMedGoogle Scholar
  252. 252.
    Huang YT, Yao CH, Way CL et al (2013) Diallyl trisulfide and diallyl disulfide ameliorate cardiac dysfunction by suppressing apoptotic and enhancing survival pathways in experimental diabetic rats. J Appl Physiol 114:402–410PubMedGoogle Scholar
  253. 253.
    Schramm A, Matusik P, Osmenda G, Guzik TJ (2012) Targeting NADPH oxidases in vascular pharmacology. Vasc Pharmacol 56:216–231Google Scholar
  254. 254.
    Cayatte AJ, Rupin A, Oliver-Krasinski J et al (2001) S17834, a new inhibitor of cell adhesion and atherosclerosis that targets NADPH oxidase. Arterioscler Thromb Vasc Biol 21:1577–1584PubMedGoogle Scholar
  255. 255.
    Xu S, Jiang B, Hou X et al (2011) High-fat diet increases and the polyphenol, S17834, decreases acetylation of the sirtuin-1-dependent lysine-382 on p53 and apoptotic signaling in atherosclerotic lesion-prone aortic endothelium of normal mice. J Cardiovasc Pharmacol 58:263–271PubMedCentralPubMedGoogle Scholar
  256. 256.
    Yang H, Roberts LJ, Shi MJ et al (2004) Retardation of atherosclerosis by overexpression of catalase or both Cu/Zn-superoxide dismutase and catalase in mice lacking apolipoprotein E. Circ Res 95:1075–1081PubMedGoogle Scholar
  257. 257.
    Van Assche T, Huygelen V, Crabtree MJ (2011) Targeting vascular redox biology through antioxidant gene delivery: a historical view and current perspectives. Recent Pat Cardiovasc Drug Discovery 6:89–102Google Scholar
  258. 258.
    Levonen AL, Inkala M, Heikura T et al (2007) Nrf2 gene transfer induces antioxidant enzymes and suppresses smooth muscle cell growth in vitro and reduces oxidative stress in rabbit aorta in vivo. Arterioscler Thromb Vasc Biol 27:741–747PubMedGoogle Scholar
  259. 259.
    Shuvaev VV, Ilies MA, Simone E et al (2011) Endothelial targeting of antibody-decorated polymeric filomicelles. ACS Nano 5:6991–6999PubMedCentralPubMedGoogle Scholar
  260. 260.
    Zern BJ, Chacko AM, Liu J et al (2013) Reduction of nanoparticle avidity enhances the selectivity of vascular targeting and PET detection of pulmonary inflammation. ACS Nano 7:2461–2469PubMedCentralPubMedGoogle Scholar
  261. 261.
    Pan H, Myerson JW, Hu L et al (2013) Programmable nanoparticle functionalization for in vivo targeting. FASEB J 27:255–264PubMedCentralPubMedGoogle Scholar
  262. 262.
    Hood E, Simone E, Wattamwar P, Dziubla T, Muzykantov V (2011) Nanocarriers for vascular delivery of antioxidants. Nanomedicine 6:1257–1272PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Basel 2014

Authors and Affiliations

  1. 1.Section of Molecular Medicine, Department of Internal MedicineUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  2. 2.Department of Biochemistry and Molecular BiologyUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA

Personalised recommendations