List of oxygen (ROS) and nitrogen (RNS) reactive species commonly found in normal and pathological tissues.
A tumor consists of a population of rapidly dividing and growing cancer cells. Cancer cells have lost their ability to divide in a controlled fashion and as a consequence they rapidly accumulate mutations. In such way cancer cells (or sub-populations of cancer cells within a tumor) will acquire stronger proliferative capacity . Tumors cannot grow beyond a certain size due to a lack of oxygen and other essential nutrients. Tumors cells have then acquired a specific feature that is to induce blood vessel growth, a process called tumor angiogenesis. Tumor angiogenesis is a necessary and required step for transition from a small harmless cluster of cells to a large tumor . The early induction of tumor vasculature is termed “angiogenic switch”, that occurs when a tumor mass reaches about dimensions of 2 mm2 and moves towards progression. The “angiogenic switch” is a rate-limiting step for tumor growth that is not limited at earliest stages, but occurs also at different stages of tumor-progression. The angiogenic switch induces angiogenic sprouting and new vessels formation and maturation. Activation of angiogenesis in premalignant lesions and dormant metastasis is mandatory for tumor survival. The fact that tumor mass is depending on angiogenesis has driven the medical research towards the characterization of molecular pathways and cellular dynamics for the induction and regulation of angiogenesis.
Tumor angiogenesis is regulated by several growth factors (EGF, TGFα, bFGF, VEGF). Induction of these angiogenic factors is triggered by various stresses . For instance, tissue hypoxia exerts its pro-angiogenic action through various angiogenic factors, the most notable is VEGF (vascular endothelial growth factor), which has been mainly associated with initiating the process of angiogenesis through the recruitment and proliferation of endothelial cells . Recently, reactive oxygen species (ROS) have been found to stimulate angiogenic response in the normal and pathological angiogenesis. ROS can cause tissue injury in one hand and promote tissue repair in another hand by promoting angiogenesis. It thus appears that after causing injury to the cells, ROS promptly initiate the tissue repair process by triggering angiogenic response. Recently, it has been reported that redox signaling may influence pathological angiogenesis as well [5,6].
2. Redox signaling in normal and pathological angiogenesis
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are important in regulation of cell survival. In general, moderate levels of ROS/RNS functions as signals to promote cell proliferation and survival, whereas severe increase of ROS/RNS can induce cell death. Under physiologic conditions, the balance between generation and elimination of ROS/RNS maintains the proper function of redox-sensitive signaling proteins. Normally, the redox homeostasis ensures that cells respond properly to endogenous and exogenous stimuli. However, when the redox homeostasis is disturbed, oxidative stress may lead to aberrant cell death and contribute to disease development .
Reactive species are highly reactive chemical molecules or ions, characterized by unpaired electrons that react with other molecules in order to stabilize their electron configuration and gain a more stable state. Consequently, the reaction of ROS/RNS with cellular molecules is a damaging reaction of oxidation. Oxidized molecules are dysfunctional and may induce cell death. Initially, the presence of ROS/RNS was linked only to cellular damage and cell degenerative processes. However, accumulating evidences derived from the characterization of mechanisms for buffering and regulating reactive species opened the possibility that oxidative species are important for cellular homeostasis. Reactive species had been also described as second messenger molecules and their interaction with molecules is identified as a post-translational modification (i.e. S- nitrosylation of proteins) that can trigger a specific intracellular signal. At the present, the evidence is that a tight regulation of pro-oxidative species levels is essential for cellular homeostasis and that such regulatory mechanism is fundamental to maintain a safe redox state and activate related redox signaling pathways .
In vascular beds, the redox state is mainly modulated by oxygen concentration and by mechanical forces (i.e. shear stress caused by blood flow) . In normal conditions oxygen levels are constant and essential to guarantee sufficient provision for tissues oxygenation. Mechanisms for sensing oxygen tension are based on redox-mediated signaling. During normoxic conditions the transcription factor HIF1α (hypoxia inducible factor) is degraded in a ROS-dependent manner, while during hypoxia the concentration of oxygen is lower and ROS levels are differentially modulated. Consequently, HIF1α couples with HIF1β and activates transcription of genes involved in angiogenesis, vascular remodeling and cell proliferation .
Redox signaling events are also activated in endothelial cells during normal angiogenesis for sensing mechanical forces. Shear forces are constantly present on endothelial cells where regulate cell proliferation, survival and migration. Vascular forces exercise a mechanical stimulus that is perceived by endothelial cells and translated into intracellular molecular pathways. Therefore, concomitant to shear forces there is an upregulation in production of RNS and ROS. In adult ECs, the mechanical oscillatory shear stress induces the activation of specific antioxidant enzymes or proteins like peroxiredoxins (Prx) that act as “mechano-sensitive antioxidants” . Moreover, specific antioxidant and protective genes are induced. Shear stress causes upregulation of specific “antioxidant transcriptional factors” Nrf2 and ATF in developing embryonic vasculature as well as in adult ECs . Most of the molecules with oxidative properties that modulate endothelial cell homeostasis in normal conditions are included in redox molecular pathways that are altered in pathogenic angiogenesis . There are specific oxidized products or redox sensitive proteins that behave differentially. ROS-activated factors play different role in context of pathologic angiogenesis or normal angiogenesis. The ATM kinase protein, which is involved in regulation of endothelial cells survival and proliferation is activated in tumor condition under upregulation of ROS and promotes new vessel formation, while it is not activated in normal vasculature . Oxidative stress triggered by inflammation in tumor conditions (i.e. human melanoma) causes lipid peroxidation with consequent accumulation of an oxidized compound: ω-(2-carboxyethyl)-pyrrole (CEP). The CEP acts as a ligand for Toll-like receptor 2 (TLR2) and induces angiogenesis independently from VEGF . Similarly, oxidized lipid (carboxyalkyl pyrroles, CAPs) molecules bind to their TLRs receptors and activate angiogenesis in some specific pathological conditions such us age related macular degeneration .
In the following three different paragraphs we will define the cellular systems regulating redox signaling and how they control molecules and factors clearly involved in angiogenesis. In addition, here we plan to present paragraphs about main sources for production of oxidative species and systems for counteract their products and maintenance of an equilibrated cell redox state. Finally, we will describe molecules sensitive to redox signaling that are known for being part of established pathway for tumor angiogenesis signaling.
3. Molecules generating oxidative species in endothelial cells
In endothelial cells the endogenous production of pro-oxidative species is mainly generated by four different enzymes: NADPH oxidases (NOX), Cyclooxygenases (COX), Xanthine oxidoreductase (XOR), and dysfunctional endothelial NOS (eNOS).
Together with these enzymes the mitochondrial electron transport chain (ETC) has been recognized as responsible for pro-oxidative species production. The mitochondrial respiratory chain is one of the first sources of pro-oxidative species to have been characterized in cells. Mechanism through witch oxidative species are produced in mitochondria are widely described as side products of ETC [53,54]. As it has been described ETC consists in an electron flow among different protein complexes in the inner mitochondria membranes. Electrons from NADPH are transferred NADPH-ubiquinone oxidoreductase complex I which consequently transfer electrons downstream to complex II. Then, electrons according to electrochemical gradients flow to complexes III and IV. The final step of the chain is the reduction of oxygen to water, however it has been quantified that about 1-4% of oxygen fails to be properly reduced and superoxide is produced as consequence. Dysfunctional ETC leads to high levels of ROS in mitochondria that are reported as cytotoxic, however this condition has been also associated with induction of pro-angiogenic signaling . In vitro and in vivo treatments with inhibitors of ETC (i.e. rotenone) inhibits VEGF -induced signaling and vascular walls remodeling  suggesting that ETC may play a role in redox signaling in normal and pathological angiogenesis.
4. Cellular systems for counterbalance oxidative species in angiogenesis: Natural antioxidants and scavenging systems
4.1. Antioxidant enzymes
In order to limit oxidative stress levels cells are armed with a series of enzymes and molecules. Important enzymes for degradation of hydrogen peroxide and superoxide are family of superoxide dismutase (SOD), catalase (CAT), peroxiredoxins (PRX), thioredoxin (TRX) and gluthatione peroxidase (GPx). All these enzymes play a critical role in modulation redox signaling.
The H2O2 generated by SOD1 is actively produced in endosomes under inflammation signals and activates NF-kB. Moreover such H2O2 generated by SOD1 is particularly important in endothelial cells where acts as endothelium–derived hyperpolarization factor (EDHF). It has been demonstrated that in the tumorigenic context, SOD1 overexpression promotes angiogenesis and tumor growth. Also the H2O2 generated by SOD2 is important for endothelium. It has been demonstrated that SOD2 overexpression favorites Akt pathway activation and enhances vessels formations
4.2. Antioxidant molecules
Recent evidence suggests that many natural
5. Angiogenic molecules regulated by redox signaling
6. Conclusion: Manipulating redox signaling as anti-tumor angiogenesis therapy
Increased generation of reactive oxygen species (ROS) and an altered redox status have long been observed in cancer cells, and recent studies suggest that this biochemical property of cancer cells can be exploited for therapeutic benefits. Cancer cells in advanced stage tumors frequently exhibit multiple genetic alterations and high oxidative stress, suggesting that it might be possible to preferentially eliminate these cells by pharmacological ROS insults .
Reactive oxygen species (ROS) might function as a double-edged sword in endothelial cells. A moderate increase of ROS may promote cell proliferation and survival. However, when the increase of ROS reaches a certain level (the toxic threshold), it may overwhelm the antioxidant capacity of the cell and trigger cell death. Under physiological conditions, normal endothelial cells maintain redox homeostasis with a low level of basal ROS by controlling the balance between ROS generation (pro-oxidants) and elimination (antioxidant capacity). Endothelial cells in normal vessels can tolerate a certain level of exogenous oxidative stress owing to their ‘reserve’ antioxidant capacity, which can be mobilized to prevent the ROS level from reaching the cell-death threshold. In In endothelial cells of tumor vessels the increase in ROS generation from metabolic abnormalities and oncogenic signaling may trigger a redox adaption response. This response leads to an upregulation of antioxidant capacity and a shift of redox dynamics that maintain the ROS levels below the toxic threshold. As such, tumor angiogenic cells would be more dependent on the antioxidant system and more vulnerable to further oxidative stress induced by exogenous ROS-generating agents or compounds that inhibit the antioxidant system. A further increase of ROS stress in these cancer cells using exogenous ROS-modulating agents is likely to cause elevation of ROS above the threshold level, leading to cell death. This might constitute a biochemical basis to design therapeutic strategies to selectively kill tumor angiogenic cells using ROS-mediated mechanisms [119-121].
The role of redox signaling in tumor angiogenesis is not yet completely characterized. Although converse mechanisms are postulated about how oxidative species recruit new blood vessels for tumor progression, it is well established redox signaling modulates angiogenesis. Analysis and characterization of molecules that sustain redox signaling is a new opportunity for set up innovative strategies of anti-cancer therapy (Figure 1).
AcknowledgmentsWe 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 lab for support and discussion. MMS is supported by grants from HFSP, Marie Curie IRG, Telethon and AIRC.
Holland AJ, Cleveland DW.Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis. Nat Rev Mol Cell Biol 2009; 10(7): 478-87
Albini A, Tosetti F, Li VW, Noonan DM, Li WW. Cancer prevention by targeting angiogenesis. Nat . Rev Clin Oncol 2012; 9(9):498-509. http://www.ncbi.nlm.nih.gov/pubmed/22850752
Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000; 407(6801):249– 257.
Fraisl P, Mazzone M, Schmidt T, Carmeliet P. Regulation of angiogenesis by oxygen and metabolism. Dev Cell. 2009; 16(2):167-79. http://www.ncbi.nlm.nih.gov/pubmed/19217420
Wu WS. The signaling mechanism of ROS in tumor progression. Cancer Metastasis Rev. 2006 Dec; 25(4):695-705. http://www.ncbi.nlm.nih.gov/pubmed/17160708
Blanchetot C, Boonstra J. The ROS-NOX connection in cancer and angiogenesis. Crit Rev Eukaryot Gene Expr 2008; 18(1):35-45.
Fridovich I. The biology of oxygen radicals. Science 1978; 201(4359):875–80.
Xia C, Meng Q, Liu LZ, Rojanasakul Y, Wang XR, Jiang BH. Reactive oxygen species regulate angiogenesis and tumor growth through vascular endothelial growth factor. Cancer Res 2007; 67(22):10823-30. http://www.ncbi.nlm.nih.gov/pubmed/18006827
Trachootham D, Lu W, Ogasawara MA, Nilsa RD, Huang P. Redox regulation of cell survival. Antioxid Redox Signal 2008;10(8):1343-74. http://www.ncbi.nlm.nih.gov/pubmed/18522489
Cai H, Garrison DG. Endothelial dysfunction in cardiovascular diseases. The role of oxidant stress. Circ. Res 2000. 87: 840–4.
Noguchi N, Jo H. Redox going with vascular shear stress. Antioxid Redox Signal 2011; 15(5):1367-8.
Hirota K, Semenza GL. Regulation of angiogenesis by hypoxia-inducible factor 1. Crit Rev Oncol Hematol 2006; 59(1):15-26.
Mowbray AL, Kang DH, Rhee SG, Kang SW, Jo H. Laminar shear stress up-regulates peroxiredoxins (PRX) in endothelial cells: PRX 1 as a mechanosensitive antioxidant. J Biol Chem 2008; 283(3):1622-7.
He CH, Gong P, Hu B, Stewart D, Choi ME, Choi AM, Alam J. Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein. Implication for heme oxygenase-1 gene regulation. J Biol Chem 2001; 276(24):20858-65.
Vurusaner B, Poli G, Basaga H. Tumor suppressor genes and ROS: complex networks of interactions.Free Radic Biol Med 2012; 52(1):7-18. http://www.ncbi.nlm.nih.gov/pubmed/22019631
Okuno Y, Nakamura-Ishizu A, Otsu K, Suda T, Kubota Y. Pathological neoangiogenesis depends on oxidative stress regulation by ATM. Nat Med. 2012. doi: 10.1038/nm.2846.
West XZ, Malinin NL, Merkulova AA, Tischenko M, Kerr BA, Borden EC, Podrez EA, Salomon RG, Byzova TV. Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands. Nature 2010; 467(7318):972-6.
Ebrahem Q, Renganathan K, Sears J, Vasanji A, Gu X, Lu L, Salomon RG, Crabb JW, Anand-Apte B. Carboxyethylpyrrole oxidative protein modifications stimulate neovascularization: Implications for age-related macular degeneration. Proc Natl Acad Sci USA 2006; 103(36):13480-4. Erratum in: Proc Natl Acad Sci USA 2006; 103(42):15722.http://www.ncbi.nlm.nih.gov/pubmed/16938854
Lambeth JD . NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 2004; 4: 181–9.
Ushio-Fukai M, Alexander RW. Reactive oxygen species as mediators of angiogenesis signaling: role of NAD(P)H oxidase. Mol Cell Biochem 2004; 264 (1–2):85–97.
Lambeth JD, Kawahara T, and Diebold B. Regulation of Nox and Duox enzymatic activity and expression. Free Radic Biol Med 2007;43: 319–31.
Ushio-Fukai M. VEGF signaling through NADPH oxidase-derived ROS.Antioxid Redox Signal 2007;9(6):731-9. http://www.ncbi.nlm.nih.gov/pubmed/17511588
Lassègue B, San Martín A, Griendling KK. Biochemistry, physiology, and pathophysiology of NADPH oxidases in the cardiovascular system. Circ Res 2012;110(10):1364-90. http://www.ncbi.nlm.nih.gov/pubmed/22581922
Ushio-Fukai M. Redox signaling in angiogenesis: role of NADPH oxidase.Cardiovasc Res 2006; 71(2):226-35. http://www.ncbi.nlm.nih.gov/pubmed/16781692
Arbiser JL, Petros J, Klafter R, Govindajaran B, McLaughlin ER, Brown LF, Cohen C, Moses M, Kilroy S, Arnold RS, Lambeth JD. Reactive oxygen generated by Nox1 triggers the angiogenic switch. Proc Natl Acad Sci USA 2002;99(2):715–20.
Ushio-Fukai M, Tang Y, Fukai T, Dikalov S, Ma Y, Fujimoto M, Quinn MT, Pagano PJ, Johnson C, Alexander RW. Novel role of gp91phox-containing NAD(P)H oxidase in vascular endothelial growth factor-induced signaling and angiogenesis. Circ Res 2002;91:1160–7.
Datla SR, Peshavariya H, Dusting GJ, Jiang F. Important Role of Nox4 Type NADPH Oxidase in Angiogenic Responses in Human Microvascular Endothelial Cells In Vitro. Arterioscler Thromb Vasc Biol 2007; 27(11):2319-24.
BelAiba RS, Djordjevic T, Petry A, Diemer K, Bonello S, Banfi B, Hess J, Pogrebniak A, Bickel C, Gorlach A. NOX5 variants are functionally active in endothelial cells. Free Radic Biol Med 2007; 42(4):446–59.
Ushio-Fukai M, Nakamura Y. Reactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy. Cancer Lett 2008; 266(1):37-52. http://www.ncbi.nlm.nih.gov/pubmed/18406051
The lipid library. Lipid Chemistry, Biology, Technology & Analysis. AOCS. http://lipidlibrary.aocs.org/index.html (accessed 28 September 2012).
He T, Lu T, d'Uscio LV, Lam CF, Lee HC, Katusic ZS. Angiogenic function of prostacyclin biosynthesis in human endothelial progenitor cells. Circ Res. 2008;103(1):80-8.
Kawabe J, Yuhki K, Okada M, Kanno T, Yamauchi A, Tashiro N, Sasaki T, Okumura S, Nakagawa N, Aburakawa Y, Takehara N, Fujino T, Hasebe N, Narumiya S, Ushikubi F. Prostaglandin I2 promotes recruitment of endothelial progenitor cells and limits vascular remodeling. Arterioscler Thromb Vasc Biol 2010; 30(3):464-70.
Gupta RA, Tan J, Krause WF, Geraci MW, Willson TM, Dey SK, DuBois RN. Prostacyclin-mediated activation of peroxisome proliferator-activated receptor delta in colorectal cancer. Proc Natl Acad Sci USA 2000;97(24):13275-80.
Cathcart, M.C. et al. (2010) The role of prostacyclin synthase and thromboxane synthase signaling in the development and progression of cancer. Biochim. Biophys. Acta 1805, 153–166
Greenhough A, Smartt HJ, Moore AE, Roberts HR, Williams AC, Paraskeva C, Kaidi A. The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis 2009;30(3):377-86.
Murata T, Lin MI, Aritake K, Matsumoto S, Narumiya S, Ozaki H, Urade Y, Hori M, Sessa WC. Role of prostaglandin D2 receptor DP as a suppressor of tumor hyperpermeability and angiogenesis in vivo. Proc Natl Acad Sci USA 2008;105(50):20009-14.
Salvado MD, Alfranca A, Haeggström JZ, Redondo JM. Prostanoids in tumor angiogenesis: therapeutic intervention beyond COX-2. Trends Mol Med 2012; 18(4):233-43.
Olson JS, Ballou DP, Palmer G, Massey V. The mechanism of action of xanthine oxidase. J Biol Chem 1974; 249(14):4363-82. http://www.ncbi.nlm.nih.gov/pubmed/4367215
Parks DA, Granger DN. Xanthine oxidase: biochemistry, distribution and physiology. Acta Physiol Scand Suppl 1986;548:87–99.
Kou B, Ni J, Vatish M, Singer DR. Xanthine oxidase interaction with vascular endothelial growth factor in human endothelial cell angiogenesis Microcirculation 2008;15(3):251-67.
Ferdinandy P, Panas D, Schulz R. Peroxynitrite contributes to spontaneous loss of cardiac efficiency in isolated working rat hearts. Am J Physiol 1999; 276(6 Pt 2):H1861-7. http://www.ncbi.nlm.nih.gov/pubmed/10362664
Pérez NG, Gao WD, Marbán E. Novel myofilament Ca2+-sensitizing property of xanthine oxidase inhibitors. Circ Res 1998;83(4):423-30.http://www.ncbi.nlm.nih.gov/pubmed/9721699
Miyamoto Y, Akaike T, Yoshida M, Goto S, Horie H, Maeda H. Potentiation of nitric oxide-mediated vasorelaxation by xanthine oxidase inhibitors.Proc Soc Exp Biol Med 1996; 211(4):366-73.
Nathan C, Xie QW. Nitric oxide synthases: roles, tolls, and controls. Cell 1994;78(6):915-8. http://www.ncbi.nlm.nih.gov/pubmed/7522969
Förstermann U, Sessa WC. Nitric oxide synthases: regulation and function. Eur Heart J 2012;33(7):829-37, 837a-837d. http://www.ncbi.nlm.nih.gov/pubmed/21890489
Förstermann U. Nitric oxide and oxidative stress in vascular disease. Pflugers Arch 2010; 459(6):923-39.
Förstermann U. Oxidative stress in vascular disease: causes, defense mechanisms and potential therapies. Nat Clin Pract Cardiovasc Med 2008; 5(6):338-49. http://www.ncbi.nlm.nih.gov/pubmed/18461048
Förstermann U, Li H. Therapeutic effect of enhancing endothelial nitric oxide synthase (eNOS) expression and preventing eNOS uncoupling. Br J Pharmacol 2011;164(2):213-23. http://www.ncbi.nlm.nih.gov/pubmed/21198553
Kawasaki K, Smith RS Jr, Hsieh CM, Sun J, Chao J, Liao JK. Activation of the phosphatidylinositol 3-kinase/protein kinase Akt pathway mediates nitric oxide-induced endothelial cell migration and angiogenesis. Mol Cell Biol 2003; 23(16):5726-37. http://www.ncbi.nlm.nih.gov/pubmed/12897144
Jones MK, Tsugawa K, Tarnawski AS, Baatar D. Dual actions of nitric oxide on angiogenesis: possible roles of PKC, ERK, and AP-1. Biochem Biophys Res Commun 2004;318(2):520-8. http://www.ncbi.nlm.nih.gov/pubmed/15120632
Fukumura D, Kashiwagi S, Jain RK. The role of nitric oxide in tumour progression. Nat Rev Cancer. 2006 Jul;6(7):521-34. http://www.ncbi.nlm.nih.gov/pubmed/16794635
Jadeski LC, Lala PK. Nitric oxide synthase inhibition by N(G)-nitro-L-arginine methyl ester inhibits tumor-induced angiogenesis in mammary tumors. Am J Pathol 1999;155(4):1381-90. http://www.ncbi.nlm.nih.gov/pubmed/10514420
Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial ROS-induced ROS release: an update and review. Biochim Biophys Acta 2006;1757(5-6):509-17.
Murphy MP. How mitochondria produce reactive oxygen species. Biochem J 2009;417(1):1-13. http://www.ncbi.nlm.nih.gov/pubmed/19061483
Zhang DX, Gutterman DD. Mitochondrial reactive oxygen species-mediated signaling in endothelial cells. Am J Physiol Heart Circ Physiol 2007; 292(5):H2023-31.
Rohlena J, Dong LF, Ralph SJ, Neuzil J. Anticancer drugs targeting the mitochondrial electron transport chain. Antioxid Redox Signal 2011;15(12):2951-74. http://www.ncbi.nlm.nih.gov/pubmed/21777145
Fukai T, Ushio-Fukai M.Superoxide dismutases: role in redox signaling, vascular function, and diseases. Antioxid Redox Signal 2011;15(6):1583-606. http://www.ncbi.nlm.nih.gov/pubmed/21473702
Oshikawa J, Urao N, Kim HW, Kaplan N, Razvi M, McKinney R, Poole LB, Fukai T, Ushio-Fukai M. Extracellular SOD-derived H2O2 promotes VEGF signaling in caveolae/lipid rafts and post-ischemic angiogenesis in mice. PLoS One 2010;5(4):e10189. http://www.ncbi.nlm.nih.gov/pubmed/20422004
Morikawa K, Shimokawa H, Matoba T, Kubota H, Akaike T, Talukder MA, Hatanaka M, Fujiki T, Maeda H, Takahashi S, Takeshita A. Pivotal role of Cu,Zn-superoxide dismutase in endothelium-dependent hyperpolarization. J Clin Invest 2003;112(12):1871-9. http://www.ncbi.nlm.nih.gov/pubmed/14679182
Marikovsky M, Nevo N, Vadai E, Harris-Cerruti C. Cu/Zn superoxide dismutase plays a role in angiogenesis. Int J Cancer 2002;97(1):34-41. http://www.ncbi.nlm.nih.gov/pubmed/11774241
Groleau J, Dussault S, Haddad P, Turgeon J, Ménard C, Chan JS, Rivard A. Essential role of copper-zinc superoxide dismutase for ischemia-induced neovascularization via modulation of bone marrow-derived endothelial progenitor cells. Arterioscler Thromb Vasc Biol 2010;30(11):2173-81. http://www.ncbi.nlm.nih.gov/pubmed/20724700
Boon EM, Downs A, Marcey D. "Proposed Mechanism of Catalase". Catalase: H2O2: H2O2 Oxidoreductase: Catalase Structural Tutorial. Retrieved 2007-02-11.
Ho YS, Xiong Y, Ma W, Spector A, Ho D. "Mice Lacking Catalase Develop Normally but Show Differential Sensitivity to Oxidant Tissue Injury". J Biol Chem 2004;279(31):32804–12. http://dx.doi.org/10.1074%2Fjbc.M404800200
Grover AK, Hui J, Samson SE. Catalase activity in coronary artery endothelium protects smooth muscle against peroxide damage. Eur J Pharmacol 2000;387(1):87-91. http://www.ncbi.nlm.nih.gov/pubmed/10633165
Ellis A, Pannirselvam M, Anderson TJ, Triggle CR. Catalase has negligible inhibitory effects on endothelium-dependent relaxations in mouse isolated aorta and small mesenteric Br J Pharmacol 2003;140(7):1193-200. http://www.ncbi.nlm.nih.gov/pubmed/14597598
Glorieux C, Dejeans N, Sid B, Beck R, Calderon PB, Verrax J. Catalase overexpression in mammary cancer cells leads to a less aggressive phenotype and an altered response to chemotherapy. Biochem Pharmacol 2011;82(10):1384-90. http://www.ncbi.nlm.nih.gov/pubmed/21689642
Wood ZA, Schröder E, Robin Harris J, Poole LB. Structure, mechanism and regulation of peroxiredoxins Trends Biochem Sci 2003;28(1):32-40. http://linkinghub.elsevier.com/retrieve/pii/S0968-0004(02)00003-8
Rhee SG, Kang SW, Chang TS, Jeong W, Kim K. Peroxiredoxin, a novel family of peroxidases. IUBMB Life 2001;52(1-2):35-41. http://www.ncbi.nlm.nih.gov/pubmed/11795591
Miki H, Funato Y. Regulation of intracellular signalling through cysteine oxidation by reactive oxygen species. J Biochem 2012;151(3):255-61. http://www.ncbi.nlm.nih.gov/pubmed/22287686
Neumann CA, Krause DS, Carman CV, Das S, Dubey DP, Abraham JL, Bronson RT, Fujiwara Y, Orkin SH, Van Etten RA. Essential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defence and tumour suppression. Nature 2003;424 (6948): 561–5. http://dx.doi.org/10.1038%2Fnature01819
Han YH, Kim SU, Kwon TH, Lee DS, Ha HL, Park DS, Woo EJ, Lee SH, Kim JM, Chae HB, Lee SY, Kim BY, Yoon do Y, Rhee SG, Fibach E, Yu DY. Peroxiredoxin II is essential for preventing hemolytic anemia from oxidative stress through maintaining hemoglobin stability. Biochem Biophys Res Commun 2012;426(3):427-32.
Lee S, Kim SM, Lee RT. Thioredoxin and Thioredoxin Target Proteins: From Molecular Mechanisms to Functional Significance. Antioxid Redox Signal. 2012.
Matsui M, Oshima M, Oshima H, Takaku K, Maruyama T, Yodoi J, Taketo MM. Early embryonic lethality caused by targeted disruption of the mouse thioredoxin gene. Dev Biol. 1996; 178(1):179-85.
Nonn L, Williams RR, Erickson RP, Powis G. The absence of mitochondrial thioredoxin 2 causes massive apoptosis, exencephaly, and early embryonic lethality in homozygous mice. Mol Cell Biol. 2003 Feb;23(3):916-22.
Dunn LL, Buckle AM, Cooke JP, Ng MK. The emerging role of the thioredoxin system in angiogenesis. Arterioscler Thromb Vasc Biol. 2010;30(11):2089-98.
Biaglow JE, Miller RA. The thioredoxin reductase/thioredoxin system: novel redox targets for cancer therapy. Cancer Biol Ther. 2005; 4(1):6-13.
Lubos E, Loscalzo J, Handy DE. Glutathione peroxidase-1 in health and disease: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal. 2011;15(7):1957-97. http://www.ncbi.nlm.nih.gov/pubmed/21087145
Thomas JP, Geiger PG, Maiorino M, Ursini F, Girotti AW. Enzymatic reduction of phospholipid and cholesterol hydroperoxides in artificial bilayers and lipoproteins.Biochim Biophys Acta1990;1045(3):252-60. http://www.ncbi.nlm.nih.gov/pubmed/2386798
Ursini F, Maiorino M, Valente M, Ferri L, Gregolin C. Purification from pig liver of a protein which protects liposomes and biomembranes from peroxidative degradation and exhibits glutathione peroxidase activity on phosphatidylcholine hydroperoxides. Biochim Biophys Acta. 1982 Feb 15;710(2):197-211.
Godeas C, Tramer F, Micali F, Soranzo M, Sandri G, Panfili E. Distribution and possible novel role of phospholipid hydroperoxide glutathione peroxidase in rat epididymal spermatozoa. Biol Reprod 1997;57(6):1502-8. http://www.ncbi.nlm.nih.gov/pubmed/9408261
Olson GE, Whitin JC, Hill KE, Winfrey VP, Motley AK, Austin LM, Deal J, Cohen HJ, Burk RF. Extracellular glutathione peroxidase (Gpx3) binds specifically to basement membranes of mouse renal cortex tubule cells. Am J Physiol Renal Physiol 2010;298(5):F1244-53.
Yu YP, Yu G, Tseng G, Cieply K, Nelson J, Defrances M, Zarnegar R, Michalopoulos G, Luo JH. Glutathione peroxidase 3, deleted or methylated in prostate cancer, suppresses prostate cancer growth and metastasis. Cancer Res 2007;67(17):8043-50.
Esworthy RS, Mann JR, Sam M, Chu FF. Low glutathione peroxidase activity in Gpx1 knockout mice protects jejunum crypts from gamma-irradiation damage. Am J Physiol Gastrointest Liver Physiol 2000;279(2):G426-36. http://www.ncbi.nlm.nih.gov/pubmed/10915653
Lei XG, Cheng WH, McClung JP. Metabolic regulation and function of glutathione peroxidase-1. Annu Rev Nutr 2007;27:41-61. http://www.ncbi.nlm.nih.gov/pubmed/17465855
De Haan JB, Crack PJ, Flentjar N, Iannello RC, Hertzog PJ, Kola I. An imbalance in antioxidant defense affects cellular function: the pathophysiological consequences of a reduction in antioxidant defense in the glutathione peroxidase-1 (Gpx1) knockout mouse. Redox Rep 2003;8(2):69-79. http://www.ncbi.nlm.nih.gov/pubmed/12804009
Wong CH, Abeynaike LD, Crack PJ, Hickey MJ. Divergent roles of glutathione peroxidase-1 (Gpx1) in regulation of leukocyte-endothelial cell interactions in the inflamed cerebral microvasculature. Microcirculation 2011;18(1):12-23. http://www.ncbi.nlm.nih.gov/pubmed/21166922
Lubos E, Loscalzo J, Handy DE. Glutathione peroxidase-1 in health and disease: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 2011;15(7):1957-97.
Bors W, Heller W, Michel C and Saran M. Flavonoids as antioxidants: determination of radical Scavenging efficiencies. Methods in Enzymology 1990; 186: 343-55.
Duffy SJ, Keaney JF Jr, Holbrook M, Gokce N, Swerdloff PL, Frei B, Vita JA. Short- and long-term black tea consumption reverses endothelial dysfunction in patients with coronary artery disease. Circulation 2001;104(2):151-6.
Scoditti E, Calabriso N, Massaro M, Pellegrino M, Storelli C, Martines G, De Caterina R, Carluccio MA. Mediterranean diet polyphenols reduce inflammatory angiogenesis through MMP-9 and COX-2 inhibition in human vascular endothelial cells: A potentially protective mechanism in atherosclerotic vascular disease and cancer. Arch Biochem Biophys 2012; 527(2):819.
Bagchi D, Sen CK, Bagchi M. Anti-angiogenic, antioxidant, and anti-carcinogenic properties of a novel anthocyanin-rich berry extract formula. Atalay M. Biochemistry 2004;69(1):75-80.
Yant LJ, Ran Q, Rao L, Van Remmen H, Shibatani T, Belter JG, Motta L, Richardson A, Prolla TA. The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults. Free Radic Biol Med 2003;34(4):496-502.
Riccioni G, D'Orazio N, Salvatore C, Franceschelli S, Pesce M, Speranza L. Carotenoids and vitamins C and E in the prevention of cardiovascular disease. Int J Vitam Nutr Res 2012;82(1):15-26.
Emmanuele V, López LC, Berardo A, Naini A, Tadesse S, Wen B, D'Agostino E, Solomon M, DiMauro S, Quinzii C, Hirano M. Heterogeneity of coenzyme Q10 deficiency: patient study and literature review. Arch Neurol 2012;69(8):978-83.
Dulak J, Loboda A, Jozkowicz A. Effect of heme oxygenase-1 on vascular function and disease. Curr Opin Lipidol 2008;19(5):505-12.
Zhou S, Ye W, Zhang M, Liang J. The effects of nrf2 on tumor angiogenesis: a review of the possible mechanisms of action. Crit Rev Eukaryot Gene Expr 2012;22(2):149-60.
Shibuya M. Tyrosine Kinase Receptor Flt/VEGFR Family: Its Characterization Related to Angiogenesis and Cancer. Genes Cancer 2010;1(11):1119-23.
Carmeliet P. VEGF as a key mediator of angiogenesis in cancer. Oncology 2005;69 Suppl 3:4-10.
Manalo DJ, Rowan A, Lavoie T, Natarajan L, Kelly BD, Ye SQ, Garcia JG, Semenza GL. Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood 2005;105(2):659-69.
Tuder RM, Flook BE, Voelkel NF. Increased gene expression for VEGF and the VEGF receptors KDR/Flk and Flt in lungs exposed to acute or to chronic hypoxia. Modulation of gene expression by nitric oxide. J Clin Invest 1995;95(4):1798-807.
Loges S, Mazzone M, Hohensinner P, Carmeliet P. Silencing or fueling metastasis with VEGF inhibitors: antiangiogenesis revisited. Cancer Cell 2009;15(3):167-70.
Reiss Y. Angiopoietins. Recent Results Cancer Res 2010;180:3-13.
Kim YM, Kim KE, Koh GY, Ho YS, Lee KJ. Hydrogen peroxide produced by angiopoietin-1 mediates angiogenesis. Cancer Res 2006;66(12):6167-74.
Zhu P, Tan MJ, Huang RL, Tan CK, Chong HC, Pal M, Lam CR, Boukamp P, Pan JY, Tan SH, Kersten S, Li HY, Ding JL, Tan NS. Angiopoietin-like 4 protein elevates the prosurvival intracellular O2(-):H2O2 ratio and confers anoikis resistance to tumors. Cancer Cell 2011;19(3):401-15.
Dejana E, Giampietro C. Vascular endothelial-cadherin and vascular stability. Curr Opin Hematol 2012;19(3):218-23.
Walsh TG, Murphy RP, Fitzpatrick P, Rochfort KD, Guinan AF, Murphy A, Cummins PM. Stabilization of brain microvascular endothelial barrier function by shear stress involves VE-cadherin signaling leading to modulation of pTyr-occludin levels. J Cell Physiol 2011;226(11):3053-63.
Carmeliet P, Collen D. Molecular basis of angiogenesis. Role of VEGF and VE-cadherin.Ann N Y Acad Sci 2000;902:249-62.
Lin MT, Yen ML, Lin CY, Kuo ML. Inhibition of vascular endothelial growth factor-induced angiogenesis by resveratrol through interruption of Src-dependent vascular endothelial cadherin tyrosine phosphorylation. Mol Pharmacol 2003;64(5):1029-36.
Simão F, Pagnussat AS, Seo JH, Navaratna D, Leung W, Lok J, Guo S, Waeber C, Salbego CG, Lo EH. Pro-angiogenic effects of resveratrol in brain endothelial cells: nitric oxide-mediated regulation of vascular endothelial growth factor and metalloproteinases. J Cereb Blood Flow Metab. 2012;32(5):884-95.
Distler JH, Hirth A, Kurowska-Stolarska M, Gay RE, Gay S, Distler O. Angiogenic and angiostatic factors in the molecular control of angiogenesis. Q J Nucl Med 2003;47(3):149-61.
Karin M. Nuclear factor-kappaB in cancer development and progression. Nature 2006;441(7092):431-6.
Santoro MM, Samuel T, Mitchell T, Reed JC, Stainier DY. Birc2 (cIap1) regulates endothelial cell integrity and blood vessel homeostasis. Nat Genet 2007;39(11):1397-402.
Schreck R, Rieber P, Baeuerle PA. Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J 1991;10(8):2247-58.
Meyer M, Schreck R, Baeuerle PA. H2O2 and antioxidants have opposite effects on activation of NF-kappa B and AP-1 in intact cells: AP-1 as secondary antioxidant-responsive factor. EMBO J 1993;12(5):2005-15.
Ebadi M, Sharma SK, Wanpen S, Amornpan A. Coenzyme Q10 inhibits mitochondrial complex-1 down-regulation and nuclear factor-kappa B activation. J Cell Mol Med 2004;8(2):213-22.
Suzuki YJ, Mizuno M, Packer L. Signal transduction for nuclear factor-kappa B activation. Proposed location of antioxidant-inhibitable step. J Immunol 1994;153(11):5008-15.
Gloire G, Legrand-Poels S, Piette J. NF-kappaB activation by reactive oxygen species: fifteen years later. Biochem Pharmacol 2006;72(11):1493-505.
Trachootham D, Alexandre J, Huang P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 2009;8(7):579-91.
Weyemi U, Redon CE, Parekh PR, Dupuy C, Bonner WM. NADPH Oxidases NOXs and DUPXs As Putative Targets for Cancer Therapy. Anticancer Agents Med Chem 2012 Aug 27.
Tertil M, Jozkowicz A, Dulak J. Oxidative stress in tumor angiogenesis- therapeutic targets.Curr Pharm Des 2010;16(35):3877-94.
Pani G, Galeotti T, Chiarugi P. Metastasis: cancer cell's escape from oxidative stress.Cancer Metastasis Rev 2010;29(2):351-78.