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Inflammation and oxidative stress in angiogenesis and vascular disease

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Abstract

Recent evidence suggests that processes of inflammation and angiogenesis are interconnected, especially in human pathologies. Newly formed blood vessels enable the continuous recruitment of inflammatory cells, which release a variety of proangiogenic cytokines, chemokines, and growth factors and further promote angiogenesis. These series of positive feedback loops ultimately create a vicious cycle that exacerbates inflammation, transforming it into the chronic process. Recently, this concept of reciprocity of angiogenesis and inflammation has been expanded to include oxidative stress as a novel mechanistic connection between inflammation-driven oxidation and neovascularization. Production of reactive oxygen species results from activation of immune cells by proinflammatory stimuli. As oxidative stress can lead to chronic inflammation by activating a variety of transcription factors including NF-κB, AP-1, and PPAR-γ, inflammation itself has a reciprocal relationship with oxidative stress. This review discusses the recent findings in the area bridging neovascularization and oxidation and highlights novel mechanisms of inflammation- and oxidative stress-driven angiogenesis.

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References

  1. Jain RK (2003) Molecular regulation of vessel maturation. Nat Med 9:685–693

    Article  PubMed  CAS  Google Scholar 

  2. Ruegg C (2006) Leukocytes, inflammation, and angiogenesis in cancer: fatal attractions. J Leukoc Biol 80:682–684

    Article  PubMed  CAS  Google Scholar 

  3. Noonan DM, De Lerma Barbaro A, Vannini N, Mortara L, Albini A (2008) Inflammation, inflammatory cells and angiogenesis: decisions and indecisions. Cancer Metastasis Rev 27:31–40

    Article  PubMed  Google Scholar 

  4. Chung AS, Ferrara N (2011) Developmental and pathological angiogenesis. Annu Rev Cell Dev Biol 27:563–584

    Article  PubMed  CAS  Google Scholar 

  5. Kutuk O, Basaga H (2003) Inflammation meets oxidation: NF-kappaB as a mediator of initial lesion development in atherosclerosis. Trends Mol Med 9:549–557

    Article  PubMed  CAS  Google Scholar 

  6. Grivennikov SI, Karin M (2010) Inflammation and oncogenesis: a vicious connection. Curr Opin Genet Dev 20:65–71

    Article  PubMed  CAS  Google Scholar 

  7. Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883–899

    Article  PubMed  CAS  Google Scholar 

  8. Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB (2010) Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med 49:1603–1616

    Article  PubMed  CAS  Google Scholar 

  9. Guzik TJ, Korbut R, Adamek-Guzik T (2003) Nitric oxide and superoxide in inflammation and immune regulation. J Physiol Pharmacol 54:469–487

    PubMed  CAS  Google Scholar 

  10. Kundu JK, Surh YJ (2012) Emerging avenues linking inflammation and cancer. Free Radic Biol Med 52:2013–2037

    Article  PubMed  CAS  Google Scholar 

  11. Costa C, Incio J, Soares R (2007) Angiogenesis and chronic inflammation: cause or consequence? Angiogenesis 10:149–166

    Article  PubMed  Google Scholar 

  12. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23:549–555

    Article  PubMed  CAS  Google Scholar 

  13. Eltzschig HK, Carmeliet P (2011) Hypoxia and inflammation. N Engl J Med 364:656–665

    Article  PubMed  CAS  Google Scholar 

  14. Konisti S, Kiriakidis S, Paleolog EM (2012) Hypoxia—a key regulator of angiogenesis and inflammation in rheumatoid arthritis. Nat Rev Rheumatol 8:153–162

    Article  PubMed  CAS  Google Scholar 

  15. Kundu JK, Surh YJ (2008) Inflammation: gearing the journey to cancer. Mutat Res 659:15–30

    Article  PubMed  CAS  Google Scholar 

  16. Grote K, Schutt H, Schieffer B (2011) Toll-like receptors in angiogenesis. ScientificWorldJournal 11:981–991

    Article  PubMed  CAS  Google Scholar 

  17. Takeda K, Akira S (2004) TLR signaling pathways. Semin Immunol 16:3–9

    Article  PubMed  CAS  Google Scholar 

  18. Kawai T, Akira S (2006) TLR signaling. Cell Death Differ 13:816–825

    Article  PubMed  CAS  Google Scholar 

  19. West XZ, Malinin NL, Merkulova AA, Tischenko M, Kerr BA, Borden EC, Podrez EA, Salomon RG, Byzova TV (2010) Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands. Nature 467:972–976

    Article  PubMed  CAS  Google Scholar 

  20. Leibovich SJ, Chen JF, Pinhal-Enfield G, Belem PC, Elson G, Rosania A, Ramanathan M, Montesinos C, Jacobson M, Schwarzschild MA et al (2002) Synergistic up-regulation of vascular endothelial growth factor expression in murine macrophages by adenosine A(2A) receptor agonists and endotoxin. Am J Pathol 160:2231–2244

    Article  PubMed  CAS  Google Scholar 

  21. Pollet I, Opina CJ, Zimmerman C, Leong KG, Wong F, Karsan A (2003) Bacterial lipopolysaccharide directly induces angiogenesis through TRAF6-mediated activation of NF-kappaB and c-Jun N-terminal kinase. Blood 102:1740–1742

    Article  PubMed  CAS  Google Scholar 

  22. Grote K, Schuett H, Salguero G, Grothusen C, Jagielska J, Drexler H, Muhlradt PF, Schieffer B (2010) Toll-like receptor 2/6 stimulation promotes angiogenesis via GM-CSF as a potential strategy for immune defense and tissue regeneration. Blood 115:2543–2552

    Article  PubMed  CAS  Google Scholar 

  23. Paone A, Galli R, Gabellini C, Lukashev D, Starace D, Gorlach A, De Cesaris P, Ziparo E, Del Bufalo D, Sitkovsky MV et al (2010) Toll-like receptor 3 regulates angiogenesis and apoptosis in prostate cancer cell lines through hypoxia-inducible factor 1 alpha. Neoplasia 12:539–549

    PubMed  CAS  Google Scholar 

  24. Palm NW, Medzhitov R (2009) Pattern recognition receptors and control of adaptive immunity. Immunol Rev 227:221–233

    Article  PubMed  CAS  Google Scholar 

  25. Kawai T, Akira S (2005) Pathogen recognition with Toll-like receptors. Curr Opin Immunol 17:338–344

    Article  PubMed  CAS  Google Scholar 

  26. van Beijnum JR, Buurman WA, Griffioen AW (2008) Convergence and amplification of toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signaling pathways via high mobility group B1 (HMGB1). Angiogenesis 11:91–99

    Article  PubMed  CAS  Google Scholar 

  27. Filippin LI, Vercelino R, Marroni NP, Xavier RM (2008) Redox signalling and the inflammatory response in rheumatoid arthritis. Clin Exp Immunol 152:415–422

    Article  PubMed  CAS  Google Scholar 

  28. Bulua AC, Simon A, Maddipati R, Pelletier M, Park H, Kim KY, Sack MN, Kastner DL, Siegel RM (2011) Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). J Exp Med 208:519–533

    Article  PubMed  CAS  Google Scholar 

  29. Lambeth JD (2004) NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 4:181–189

    Article  PubMed  CAS  Google Scholar 

  30. Li N, Ragheb K, Lawler G, Sturgis J, Rajwa B, Melendez JA, Robinson JP (2003) Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. J Biol Chem 278:8516–8525

    Article  PubMed  CAS  Google Scholar 

  31. Kanayama A, Miyamoto Y (2007) Apoptosis triggered by phagocytosis-related oxidative stress through FLIPS down-regulation and JNK activation. J Leukoc Biol 82:1344–1352

    Article  PubMed  CAS  Google Scholar 

  32. Gorlach A, Kietzmann T, Hess J (2002) Redox signaling through NADPH oxidases: involvement in vascular proliferation and coagulation. Ann N Y Acad Sci 973:505–507

    Article  PubMed  Google Scholar 

  33. Chiarugi P, Pani G, Giannoni E, Taddei L, Colavitti R, Raugei G, Symons M, Borrello S, Galeotti T, Ramponi G (2003) Reactive oxygen species as essential mediators of cell adhesion: the oxidative inhibition of a FAK tyrosine phosphatase is required for cell adhesion. J Cell Biol 161:933–944

    Article  PubMed  CAS  Google Scholar 

  34. Thannickal VJ, Fanburg BL (2000) Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol 279:L1005–L1028

    PubMed  CAS  Google Scholar 

  35. van Wetering S, van Buul JD, Quik S, Mul FP, Anthony EC, ten Klooster JP, Collard JG, Hordijk PL (2002) Reactive oxygen species mediate Rac-induced loss of cell-cell adhesion in primary human endothelial cells. J Cell Sci 115:1837–1846

    PubMed  Google Scholar 

  36. San Martin A, Griendling KK (2010) Redox control of vascular smooth muscle migration. Antioxid Redox Signal 12:625–640

    Article  PubMed  CAS  Google Scholar 

  37. auf dem Keller U, Kumin A, Braun S, Werner S (2006) Reactive oxygen species and their detoxification in healing skin wounds. J Investig Dermatol Symp Proc 11:106–111

    Article  Google Scholar 

  38. Ushio-Fukai M (2006) Redox signaling in angiogenesis: role of NADPH oxidase. Cardiovasc Res 71:226–235

    Article  PubMed  CAS  Google Scholar 

  39. Ushio-Fukai M, Nakamura Y (2008) Reactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy. Cancer Lett 266:37–52

    Article  PubMed  CAS  Google Scholar 

  40. Waris G, Ahsan H (2006) Reactive oxygen species: role in the development of cancer and various chronic conditions. J Carcinog 5:14

    Article  PubMed  Google Scholar 

  41. Zhao W, Zhao T, Chen Y, Ahokas RA, Sun Y (2009) Reactive oxygen species promote angiogenesis in the infarcted rat heart. Int J Exp Pathol 90:621–629

    Article  PubMed  CAS  Google Scholar 

  42. Maulik N, Das DK (2002) Redox signaling in vascular angiogenesis. Free Radic Biol Med 33:1047–1060

    Article  PubMed  CAS  Google Scholar 

  43. Datla SR, Griendling KK (2010) Reactive oxygen species, NADPH oxidases, and hypertension. Hypertension 56:325–330

    Article  PubMed  CAS  Google Scholar 

  44. Armstrong AW, Voyles SV, Armstrong EJ, Fuller EN, Rutledge JC (2011) Angiogenesis and oxidative stress: common mechanisms linking psoriasis with atherosclerosis. J Dermatol Sci 63:1–9

    Article  PubMed  CAS  Google Scholar 

  45. Ushio-Fukai M, Alexander RW (2004) Reactive oxygen species as mediators of angiogenesis signaling: role of NAD(P)H oxidase. Mol Cell Biochem 264:85–97

    Article  PubMed  CAS  Google Scholar 

  46. Colavitti R, Pani G, Bedogni B, Anzevino R, Borrello S, Waltenberger J, Galeotti T (2002) Reactive oxygen species as downstream mediators of angiogenic signaling by vascular endothelial growth factor receptor-2/KDR. J Biol Chem 277:3101–3108

    Article  PubMed  CAS  Google Scholar 

  47. 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 67:10823–10830

    Article  PubMed  CAS  Google Scholar 

  48. Salomon RG (2012) Structural identification and cardiovascular activities of oxidized phospholipids. Circ Res 111:930–946

    Article  PubMed  CAS  Google Scholar 

  49. Crabb JW, Miyagi M, Gu X, Shadrach K, West KA, Sakaguchi H, Kamei M, Hasan A, Yan L, Rayborn ME et al (2002) Drusen proteome analysis: an approach to the etiology of age-related macular degeneration. Proc Natl Acad Sci U S A 99:14682–14687

    Article  PubMed  CAS  Google Scholar 

  50. Gu X, Meer SG, Miyagi M, Rayborn ME, Hollyfield JG, Crabb JW, Salomon RG (2003) Carboxyethylpyrrole protein adducts and autoantibodies, biomarkers for age-related macular degeneration. J Biol Chem 278:42027–42035

    Article  PubMed  CAS  Google Scholar 

  51. Hollyfield JG, Bonilha VL, Rayborn ME, Yang X, Shadrach KG, Lu L, Ufret RL, Salomon RG, Perez VL (2008) Oxidative damage-induced inflammation initiates age-related macular degeneration. Nat Med 14:194–198

    Article  PubMed  CAS  Google Scholar 

  52. Malinin NL, West XZ, Byzova TV (2011) Oxidation as “the stress of life”. Aging 3:906–910

    PubMed  CAS  Google Scholar 

  53. Ebrahem Q, Renganathan K, Sears J, Vasanji A, Gu X, Lu L, Salomon RG, Crabb JW, Anand-Apte B (2006) Carboxyethylpyrrole oxidative protein modifications stimulate neovascularization: Implications for age-related macular degeneration. Proc Natl Acad Sci U S A 103:13480–13484

    Article  PubMed  CAS  Google Scholar 

  54. Guo Z, Kozlov S, Lavin MF, Person MD, Paull TT (2010) ATM activation by oxidative stress. Science 330:517–521

    Article  PubMed  CAS  Google Scholar 

  55. Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421:499–506

    Article  PubMed  CAS  Google Scholar 

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

  57. Panigrahi S, Ma Y, Hong L, Gao D, West XZ, Salomon RG, Byzova TV, Podrez EA (2012) Engagement of platelet toll-like receptor 9 by novel endogenous ligands promotes platelet hyperreactivity and thrombosis. Circ Res 112:103–112

    Article  PubMed  Google Scholar 

  58. Jain RK, Duda DG, Clark JW, Loeffler JS (2006) Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat Clin Pract Oncol 3:24–40

    Article  PubMed  CAS  Google Scholar 

  59. Duda DG, Batchelor TT, Willett CG, Jain RK (2007) VEGF-targeted cancer therapy strategies: current progress, hurdles and future prospects. Trends Mol Med 13:223–230

    Article  PubMed  CAS  Google Scholar 

  60. Heath VL, Bicknell R (2009) Anticancer strategies involving the vasculature. Nat Rev Clin Oncol 6:395–404

    Article  PubMed  CAS  Google Scholar 

  61. Kerr BA, Byzova TV (2012) The dark side of the oxidative force in angiogenesis. Nat Med 18:1184–1185

    Article  PubMed  CAS  Google Scholar 

  62. Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473:298–307

    Article  PubMed  CAS  Google Scholar 

  63. Kamba T, McDonald DM (2007) Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer 96:1788–1795

    Article  PubMed  CAS  Google Scholar 

  64. Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8:592–603

    Article  PubMed  CAS  Google Scholar 

  65. Weis SM, Cheresh DA (2011) Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med 17:1359–1370

    Article  PubMed  CAS  Google Scholar 

  66. Casanovas O, Hicklin DJ, Bergers G, Hanahan D (2005) Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8:299–309

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by a research funding from NIH grant HL071625 to T.V.B. We thank Emelye Crehore for her assistance with manuscript proofreading.

Conflict of interest

The authors declare no conflict of interests. A patent describing the role of CEP has been submitted.

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Authors and Affiliations

  1. Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave., NB50, Cleveland, OH, 44195, USA

    Young-Woong Kim, Xiaoxia Z. West & Tatiana V. Byzova

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  1. Young-Woong Kim
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  2. Xiaoxia Z. West
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  3. Tatiana V. Byzova
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Corresponding author

Correspondence to Tatiana V. Byzova.

Additional information

Young-Woong Kim and Xiaoxia Z. West contributed equally to this work.

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Kim, YW., West, X.Z. & Byzova, T.V. Inflammation and oxidative stress in angiogenesis and vascular disease. J Mol Med 91, 323–328 (2013). https://doi.org/10.1007/s00109-013-1007-3

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