This Article Abstract Full Text (PDF) All Versions of this Article: 25/2/274    most recent 01.ATV.0000149143.04821.ebv1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mueller, C. F.H. Articles by Harrison, D. G. Search for Related Content PubMed PubMed Citation Articles by Mueller, C. F.H. Articles by Harrison, D. G. Related Collections Redox Mechanisms in Blood Vessels Related Article

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:274.)
© 2005 American Heart Association, Inc.

Brief Reviews

Redox Mechanisms in Blood Vessels

Cornelius F.H. Mueller; Karine Laude; J. Scott McNally; David G. Harrison

From Emory University Division of Cardiology, Department of Medicine and the Atlanta Veterans Administration Hospital, Atlanta, Ga.

Correspondence to David G. Harrison, Division of Cardiology, Emory University, 1639 Pierce Drive, WMRB 319, Atlanta, GA 30322. E-mail dharr02{at}emory.edu

Series Editor: Kathy K. Griendling

	Abstract

Top Abstract Introduction Sources of ROS in... NADPH Oxidases Xanthine Oxidase Uncoupled Endothelial Nitric... Mitochondrial Electron Transport Diverse Properties of ROS References

 
Reactive oxygen species have been implicated in the pathogenesis of virtually every stage of vascular lesion formation, hypertension, and other vascular diseases. We are currently gaining insight into important sources of reactive oxygen species in the vessel wall, including the NADPH oxidases, xanthine oxidase, uncoupled nitric oxide synthase, and mitochondrial sources. Although various reactive oxygen species have pathological roles, some serve as important signaling molecules that modulate vascular tone, growth, and remodeling. In the next several months, a series of articles in Arteriosclerosis, Thrombosis, and Vascular Biology attempt to further elucidate how reactive oxygen species are produced by vascular cells and the roles of these in vascular homeostasis. This series promises to provide a valuable update on a wide variety of issues related to the biochemistry, molecular biology, and physiology of these important and fascinating molecules.

Reactive oxygen species have been implicated in the pathogenesis of virtually every stage of vascular lesion formation, hypertension, and other vascular diseases. Upcoming series of articles in Arteriosclerosis, Thrombosis, and Vascular Biology help elucidate how reactive oxygen species are produced by vascular cells and their role in vascular homeostasis.

Key Words: NADPH oxidase • superoxide • nitric oxide synthase • xanthine oxidase • mitochondria

	Introduction

Top Abstract Introduction Sources of ROS in... NADPH Oxidases Xanthine Oxidase Uncoupled Endothelial Nitric... Mitochondrial Electron Transport Diverse Properties of ROS References

 
In the next several months, Arteriosclerosis, Thrombosis, and Vascular Biology will publish a series of reviews examining in depth the source and role of reactive oxygen species (ROS) and oxidant stress in vascular disease. Disorders such as hypercholesterolemia, hypertension, diabetes, aging, and mechanical injury are associated with increased ROS production.^1–5 The fact that these conditions contribute to >33% of the deaths and 40% of the total medical expenses in industrialized countries emphasizes the importance of understanding how oxidative stress occurs and how ROS affect the vascular system.⁶ Several enzyme systems have recently been recognized to be sources of ROS in vascular cells under pathological conditions. Experimental studies in cells and experimental animals have indicated that ROS mediate or enhance virtually every aspect of atherosclerotic lesion formation. The best-characterized of these events is oxidative modification of low-density lipoprotein, which can occur via reaction of ROS with low-density lipoprotein or via direct enzymatic modification by lipoxygenases.⁷ Beyond this, ROS can promote inflammation,⁸ alter vasomotion,⁹ activate matrix metalloproteinases,¹⁰ induce apoptosis,¹¹ cause platelet aggregation,¹² and stimulate vascular smooth muscle proliferation.¹³ All of these events are active in the atherosclerotic lesion and are thought to contribute to vascular lesion formation.

See cover

It has been, only in the past decade, widely accepted that vascular cells could produce ROS, and we are still learning a great deal about the role of the various potential enzymes, how they are regulated, and the role of oxidative stress in vascular disease. A technical problem has been that vessels do not produce ROS at levels equivalent to neutrophils; therefore, the methods commonly used for neutrophils, such as cytochrome c reduction, yield values that are only slightly above the limit of detection. This problem was overcome by the use of chemiluminescence techniques, such as lucigenin-enhanced chemiluminescence, and this entire area of research was dramatically advanced by the use of such methods. In the late 1990s, several articles appeared in which the authors showed that lucigenin-enhanced chemiluminescence could artifactually produce superoxide; however, these "test tube" experiments did not reflect the assay as used in intact vessels.¹⁴ Subsequently, numerous methods including electron spin resonance, dihydroethidium oxidation, other chemiluminescence methods, and even cytochrome c reduction have been used to confirm the results observed with lucigenin-enhanced chemiluminescence. Further, assays of hydrogen peroxide often provide results that mirror these measures of superoxide production in diseased vessels. All of these have confirmed an increased ROS production by vessels in the setting of disorders like hypercholesterolemia, diabetes, and hypertension.^15–17

	Sources of ROS in Vascular Cells

Top Abstract Introduction Sources of ROS in... NADPH Oxidases Xanthine Oxidase Uncoupled Endothelial Nitric... Mitochondrial Electron Transport Diverse Properties of ROS References

 
This special series of ATVB provides an opportunity to review our current understanding of how ROS are produced in the vessel wall. Although there are numerous enzyme systems that can potentially produce ROS in the vessel wall, 4 enzyme systems seem to predominate. These include the NADPH oxidases, xanthine oxidase, uncoupled NO synthase, and mitochondrial sources. A recurring theme is that there appears to be substantial interplay between these sources, such that activation of one can enhance activity of others (Figure). This can lead to feed-forward processes, which further augment ROS production and oxidant stress. These interactions are further discussed in the following paragraphs.

View larger version (32K): [in this window] [in a new window]   Known sources of reactive oxygen species (ROS) and potential interactions. In vascular cells, predominant sources of ROS include the NADPH oxidase, xanthine oxidase, uncoupled nitric oxide synthase, and mitochondrial electron transport. The Nox proteins are the catalytic component of the NADPH oxidase and together with p22phox comprise the membrane cytochrome. Shown also is the oxygenase domain of eNOS, which in the absence of tetrahydrobiopterin (BH4) can produce large amounts of superoxide. ROS produced from the NADPH oxidase can promote oxidation of BH4 and increase the relative levels of xanthine oxidase in the endothelium. Hydrogen peroxide and lipid peroxides are also capable of stimulating the NADPH oxidases to further produce superoxide.

	NADPH Oxidases

Top Abstract Introduction Sources of ROS in... NADPH Oxidases Xanthine Oxidase Uncoupled Endothelial Nitric... Mitochondrial Electron Transport Diverse Properties of ROS References

 
The NADPH oxidase enzymes, also known as the Nox enzymes, represent a major source of ROS in vascular cells. The Nox proteins represent the catalytic subunits of these enzymes and vary in terms of their mode of activation and need for cofactor activation.¹⁸ Nox1 protein levels are quite low in vascular cells, but can be induced by stimuli such as PDGF, angiotensin II, and serum.¹⁸ Nox2, previously known as gp91^phox, is the large catalytic subunit of the phagocyte cytochrome b558. It is expressed in endothelial and adventitial cells of large vessels and in the vascular smooth muscle cells of smaller vessels.^19–22 Nox4 is constitutively expressed and constitutively active in vascular smooth muscle and endothelial cells.^23,24 Current understanding is that all the Nox enzymes require p22^phox, which serves as a docking protein for other subunits and stabilizes the Nox proteins.²⁵ A variety of pathological stimuli, such as angiotensin II, stretch, endothelin-1, thrombin, and catecholamines acutely activate the NADPH oxidases in vascular smooth muscle and endothelial cells. The biochemical pathway whereby angiotensin II activates the NADPH oxidase involves activation of the tyrosine kinase c-Src, transactivation of the EGF receptor, and ultimately activation and translocation of the small g protein Rac-1.²⁶ Activation of Nox1 and Nox2 also require translocation of cytoplasmic subunits, including p47^phox,²⁷ or analogues of p47^phox and p67^phox termed NoxO1 and NoxA1.^28,29 Interestingly, pathophysiological stimuli such as angiotensin II, hypercholesterolemia, growth factors, and serum can also increase expression of several of the NADPH oxidase subunits, including p22^phox, Nox1, and Nox4, further promoting an increase in ROS production.¹⁸ The biochemical pathways regulating expression of these subunits have not been elucidated. Nevertheless, activation and increased expression of these Nox-based oxidases are clearly very important in modulating oxidant stress in vascular disease. These issues are discussed in an upcoming review by Dr Francis Miller. It should be noted that Dr Miller, working in collaboration with Dr Neal Weintraub, first showed that hydrogen peroxide and lipid peroxides can stimulate activity of the NADPH oxidases in vascular smooth muscle cells, leading to a feed-forward increase in ROS production.^30,31

	Xanthine Oxidase

Top Abstract Introduction Sources of ROS in... NADPH Oxidases Xanthine Oxidase Uncoupled Endothelial Nitric... Mitochondrial Electron Transport Diverse Properties of ROS References

 
Another important source of ROS in mammalian cells is the xanthine oxidoreductase. Xanthine oxidoreductase exists in 2 forms, as xanthine dehydrogenase (XDH) and as xanthine oxidase (XO).³² XDH uses NAD⁺ to receive electrons from hypoxanthine and xanthine, yielding NADH and uric acid. In contrast, XO uses oxygen as an electron acceptor from these same substrates to form and hydrogen peroxide. The ratio of XO to XDH in the cell is therefore critical to determine the amount of ROS produced by these enzymes. Conversion of XDH to XO is stimulated by inflammatory cytokines, like tumor necrosis factor-, and also by oxidation of critical cysteine residues by oxidants, such as peroxynitrite.^33,34 Recently, we have shown in bovine and mouse aortic endothelial cells that the relative levels of these is markedly altered by the presence of a functioning NADPH oxidase, such that in cells with an absence of the NADPH oxidase, the levels of XO are extremely low.^35,36 In more recent studies, we have found that this is mediated by hydrogen peroxide released from the NADPH oxidase. Thus, this regulation represents a second situation in which cellular production of ROS from the NADPH oxidase further begets ROS production.

There is substantial debate as to whether XDH is expressed. Immunohistochemical studies of normal human tissues have failed to demonstrate XDH in endothelial cells or other cardiovascular tissues.³⁶ In contrast, there is evidence that XO can produce ROS and affect endothelial function in humans in the setting of pathology,^15,37–39 possibly caused by stimulation of XO expression by inflammatory cytokines or other stimuli in these conditions. For example, Sohn et al have shown that hypoxia induces XO activity in human umbilical vein endothelial cells.⁴⁰ There is substantial interest in the concept that the XO present in endothelial cells originates from other organs and that the enzyme is probably taken-up via heparin binding sites.^15,41,42 Whatever the source of XO, its vascular activity correlates inversely with endothelial function in patients with heart failure and in subjects with atherosclerosis.^15,43 Dr Margaret Tarpey discusses these concepts in greater depth in her upcoming review of xanthine oxidoreductase.

	Uncoupled Endothelial Nitric Oxide Synthase

Top Abstract Introduction Sources of ROS in... NADPH Oxidases Xanthine Oxidase Uncoupled Endothelial Nitric... Mitochondrial Electron Transport Diverse Properties of ROS References

 
A third major contributor to vascular ROS generation is uncoupled endothelial nitric oxide synthase (eNOS). The normal product of this enzyme is nitric oxide (NO); however, in the absence of either L-arginine or tetrahydrobiopterin (BH₄), the NO synthases are incapable of transferring electrons to L-arginine and begin to use oxygen as a substrate for formation.⁴⁴ Uncoupling of eNOS has been demonstrated in various pathophysiological conditions including diabetes,¹⁷ hypercholesterolemia,⁴⁵ and hypertension.⁴⁶ In DOCA-salt hypertension, oxidation of BH₄ occurs as a result of ROS (particularly peroxynitrite) produced by the NADPH oxidase. Oral treatment of mice that have DOCA-salt hypertension with BH₄"re-couples" eNOS, leading to increased vascular NO production, decreased production, and lowering of blood pressure.⁴⁶ Thus, uncoupling of eNOS caused by oxidation of BH₄ represents a third mechanism whereby ROS produced by the NADPH oxidase can stimulate another enzyme to produce additional ROS in a self-perpetuating fashion.

Related to this situation, eNOS is subject to regulation by H₂O₂, which acutely activates the enzyme and, over the longer-term, increases its expression. Thus, increased expression of eNOS in the setting of oxidant stress can lead to a situation in which high levels of the uncoupled enzyme can generate even greater amounts of . It should be stressed that not all eNOS becomes uncoupled, such that some of the enzyme continues to produce NO, leading to a condition favoring production of peroxynitrite. Dr Thomas Münzel discusses NOS uncoupling in much greater detail in his upcoming review.

	Mitochondrial Electron Transport

Top Abstract Introduction Sources of ROS in... NADPH Oxidases Xanthine Oxidase Uncoupled Endothelial Nitric... Mitochondrial Electron Transport Diverse Properties of ROS References

 
In other organs and tissues, the mitochondrial electron transport chain represents the predominant source of and consequently H₂O₂. It has been estimated that between 1% and 4% of the oxygen reacting with the respiratory chain is incompletely reduced to . Defects in mitochondria DNA can be inherited or can develop as a result of disease, and have been proposed to augment ROS production by these organelles.^47,48 Interestingly, exposure of endothelial or vascular smooth muscle cells to exogenous peroxynitrite or H₂O₂ leads to mitochondrial DNA damage.⁴⁹ This represents yet another mechanism whereby oxidant stress could beget further oxidant stress.

In the vessel wall, the precise contribution of mitochondria to the total ROS production, however, remains unclear. Part of this problem relates to the fact that specific antagonists are not well-characterized. For example, rotenone is often used to inhibit mitochondrial radical production^50,51 but, in fact, is capable of having the opposite effect.^31,52 Furthermore, inhibition of mitochondrial function can dramatically alter many other aspects of cell metabolism, making results from such interventions difficult to interpret. Nevertheless, there is ample evidence that mitochondria play an important role in vascular ROS production. Stimuli such as high glucose, cyclic strain, leptin, and cigarette smoking have been shown to damage aortic mitochondrial DNA and alter mitochondrial enzyme activity. Dr Paul Schumacker’s review examines the role of mitochondria in vascular oxidant stress further.

	Diverse Properties of ROS

Top Abstract Introduction Sources of ROS in... NADPH Oxidases Xanthine Oxidase Uncoupled Endothelial Nitric... Mitochondrial Electron Transport Diverse Properties of ROS References

 
It is important to note that one should not lump all ROS together when considering the topic of oxidant stress and vascular disease. Some ROS, such as superoxide the hydroxyl radical (HO), peroxy-radicals (ROO·), and NO have unpaired electrons in their outer orbital. Others, such as H₂O₂ and peroxynitrite, do not have unpaired electrons but are oxidants. These can have very different roles. Superoxide reacts with NO in a diffusion limited fashion, leading to formation of peroxynitrite and loss of the beneficial actions of NO. This phenomenon is thought to be responsible for reduced endothelium-dependent vasodilatation in many conditions, and likely contributes to hypertension by removing the vasodilator effect of NO. Peroxynitrite is a very potent oxidant and can oxidize lipids and thiols and react with iron sulfur centers in a variety of enzymes. Whereas scavenging improves endothelium-dependent vasodilatation, it might not reduce atherosclerosis, because scavenging does not eliminate other ROS and, in fact, can enhance production of H₂O₂ (Scheme 1).⁵³

View larger version (6K): [in this window] [in a new window]   Scheme 1:

Scheme 1 is important because there is increasing evidence that H₂O₂ plays an important role in atherosclerosis. As an example, Tribble et al showed that lesion formation was not diminished in mice overexpressing Cu/Zn SOD and, in fact, was increased in direct relation to aortic Cu/Zn SOD activity.⁵⁴

Another aspect of ROS is that they are not uniformly deleterious and can have important signaling properties within the vessel wall.⁵⁵ Hydrogen peroxide, in particular, is relatively stable and uncharged so that it can easily diffuse between cells. Recently, it has become clear that endogenously produced H₂O₂ can act as an endogenous hyperpolarizing factor in both human and mouse resistance vessels.^56,57 Dr Gutterman discusses this further in his upcoming review. Hydrogen peroxide has been shown to inhibit phosphatases, and activate guanylate cyclase, and to stimulate NO production and alter gene expression. The mechanisms involved in these signaling events are varied. An important reaction is oxidation of critical cysteines to sulfenic acids, which in turn can serve as precursors to sulfonic acid and/or disulfide formation. These modifications can alter function of a number of enzymes, including phosphatases, glyceraldehyde-3-phosphate dehydrogenase, and peroxiredoxin.^58–60 Recent evidence suggests that interactions between H₂O₂ and peroxidases, especially myeloperoxidase, lead to formation of oxidizing and nitrosating species that are particularly atherogenic. Importantly, modification of proteins by these radicals alters their enzymatic function. Nitration of apolipoprotein A1 dramatically impairs its ability to participate in reverse cholesterol transport from lipid-laden macrophages, and thus reduces atheroprotective properties of high-density lipoprotein.⁶¹ Dr Hazen discusses this in detail in his review of myeloperoxidase.

Finally, it is essential that we develop a greater understanding of all the compensatory responses to prolonged oxidant stress. Recent studies from our groups have supported the concept that increased ROS production has minimal effects on vascular function and hemodynamics at baseline but can augment the response pathogenic stimuli. We have produced mice with smooth muscle-targeted overexpression of the NADPH oxidase subunit p22^phox. Overexpression of this subunit resulted in a concomitant increase in expression of Nox1 and enhanced vascular and H₂O₂ production.⁶² At baseline, these mice were normotensive and had normal vascular reactivity and histology. In response to angiotensin II, however, augmented hypertension and increased thickness of the vascular media develop in these animals.⁶³ In addition, vascular injury enhances atheroma formation in these animals.⁶⁴ Further characterization of these mice indicated that they have increased endothelial NO synthase expression, NO production, and expression of the extracellular superoxide dismutase, which likely compensate for their enhanced vascular ROS production. We have concluded from these studies that increased vascular ROS production has minimal effects in the absence of stimuli such as angiotensin II or mechanical injury, but the presence of such stimuli markedly augments pathological responses. In this regard, the compensatory responses to oxidative stress are likely critically important, and disease probably does not occur until these mechanisms fail. It remains a challenge to understand all of these compensatory mechanisms, why they fail, and what can be done to preserve their function.

Received September 27, 2004; accepted October 20, 2004.

	References

Top Abstract Introduction Sources of ROS in... NADPH Oxidases Xanthine Oxidase Uncoupled Endothelial Nitric... Mitochondrial Electron Transport Diverse Properties of ROS References

 
1. Ohara Y, Peterson TE, Harrison DG. Hypercholesterolemia increases endothelial superoxide anion production. J Clin Invest. 1993; 91: 2546–2551.

2. Rajagopalan S, Kurz S, Munzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J Clin Invest. 1996; 97: 1916–1923.[Medline] [Order article via Infotrieve]

3. Hattori Y, Kawasaki H, Abe K, Kanno M. Superoxide dismutase recovers altered endothelium-dependent relaxation in diabetic rat aorta. Am J Physiol. 1991; 261: H1086–H1094.

4. van der Loo B, Labugger R, Skepper JN, Bachschmid M, Kilo J, Powell JM, Palacios-Callender M, Erusalimsky JD, Quaschning T, Malinski T, Gygi D, Ullrich V, Luscher TF. Enhanced peroxynitrite formation is associated with vascular aging. J Exp Med. 2000; 192: 1731–1744.[Abstract/Free Full Text]

5. Laurindo FR, de Souza HP, Pedro Mde A, Janiszewski M. Redox aspects of vascular response to injury. Methods Enzymol. 2002; 352: 432–454.[Medline] [Order article via Infotrieve]

6. Lenfant C, Friedman L, Thom T. Fifty years of death certificates: the Framingham Heart Study. Ann Intern Med. 1998; 129: 1066–1067.[Free Full Text]

7. Albertini R, Moratti R, De Luca G. Oxidation of low-density lipoprotein in atherosclerosis from basic biochemistry to clinical studies. Curr Mol Med. 2002; 2: 579–592.[CrossRef][Medline] [Order article via Infotrieve]

8. Lavrovsky Y, Chatterjee B, Clark RA, Roy AK. Role of redox-regulated transcription factors in inflammation, aging and age-related diseases. Exp Gerontol. 2000; 35: 521–532.[CrossRef][Medline] [Order article via Infotrieve]

9. Harrison DG. Cellular and molecular mechanisms of endothelial cell dysfunction. J Clin Invest. 1997; 100: 2153–2157.[Medline] [Order article via Infotrieve]

10. Rajagopalan S, Meng XP, Ramasamy S, Harrison DG, Galis ZS. Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. Implications for atherosclerotic plaque stability. J Clin Invest. 1996; 98: 2572–2579.[Medline] [Order article via Infotrieve]

11. Dimmeler S, Hermann C, Galle J, Zeiher AM. Upregulation of superoxide dismutase and nitric oxide synthase mediates the apoptosis-suppressive effects of shear stress on endothelial cells. Arterioscler Thromb Vasc Biol. 1999; 19: 656–664.[Abstract/Free Full Text]

12. Yao SK, Ober JC, Gonenne A, Clubb FJ Jr, Krishnaswami A, Ferguson JJ, Anderson HV, Gorecki M, Buja LM, Willerson JT. Active oxygen species play a role in mediating platelet aggregation and cyclic flow variations in severely stenosed and endothelium-injured coronary arteries. Circ Res. 1993; 73: 952–967.[Abstract/Free Full Text]

13. Griendling KK, Ushio-Fukai M. Redox control of vascular smooth muscle proliferation. J Lab Clin Med. 1998; 132: 9–15.[CrossRef][Medline] [Order article via Infotrieve]

14. Münzel T, Afanas’ev I, Kleschyov A, Harrison D. Detection of superoxide in vascular tissue. Arterioscler Thromb Vasc Biol. 2002; 22: 1761–1768.[Abstract/Free Full Text]

15. Spiekermann S, Landmesser U, Dikalov S, Bredt M, Gamez G, Tatge H, Reepschlager N, Hornig B, Drexler H, Harrison DG. Electron spin resonance characterization of vascular xanthine and NAD(P)H oxidase activity in patients with coronary artery disease: relation to endothelium-dependent vasodilation. Circulation. 2003; 107: 1383–1389.[Abstract/Free Full Text]

16. Alp NJ, Mussa S, Khoo J, Cai S, Guzik T, Jefferson A, Goh N, Rockett KA, Channon KM. Tetrahydrobiopterin-dependent preservation of nitric oxide-mediated endothelial function in diabetes by targeted transgenic GTP-cyclohydrolase I overexpression. J Clin Invest. 2003; 112: 725–735.[CrossRef][Medline] [Order article via Infotrieve]

17. Hink U, Li H, Mollnau H, Oelze M, Matheis E, Hartmann M, Skatchkov M, Thaiss F, Stahl RA, Warnholtz A, Meinertz T, Griendling K, Harrison DG, Forstermann U, Munzel T. Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res. 2001; 88: E14–E22.

18. Lassegue B, Clempus RE. Vascular NAD(P)H oxidases: specific features, expression, and regulation. Am J Physiol Regul Integr Comp Physiol. 2003; 285: R277–R297.[Abstract/Free Full Text]

19. Gorlach A, Brandes RP, Nguyen K, Amidi M, Dehghani F, Busse R. A gp91phox containing NADPH oxidase selectively expressed in endothelial cells is a major source of oxygen radical generation in the arterial wall. Circ Res. 2000; 87: 26–32.[Abstract/Free Full Text]

20. Jones SA, O’Donnell VB, Wood JD, Broughton JP, Hughes EJ, Jones OT. Expression of phagocyte NADPH oxidase components in human endothelial cells. Am J Physiol. 1996; 271: H1626–H1634.

21. Touyz RM, Chen X, Tabet F, Yao G, He G, Quinn MT, Pagano PJ, Schiffrin EL. Expression of a functionally active gp91phox-containing neutrophil-type NAD(P)H oxidase in smooth muscle cells from human resistance arteries: regulation by angiotensin II. Circ Res. 2002; 90: 1205–1213.[Abstract/Free Full Text]

22. Wang HD, Pagano PJ, Du Y, Cayatte AJ, Quinn MT, Brecher P, Cohen RA. Superoxide anion from the adventitia of the rat thoracic aorta inactivates nitric oxide. Circ Res. 1998; 82: 810–818.[Abstract/Free Full Text]

23. Ago T, Kitazono T, Ooboshi H, Iyama T, Han YH, Takada J, Wakisaka M, Ibayashi S, Utsumi H, Iida M. Nox4 as the major catalytic component of an endothelial NAD(P)H oxidase. Circulation. 2004; 109: 227–233.[Abstract/Free Full Text]

24. Hilenski LL, Clempus RE, Quinn MT, Lambeth JD, Griendling KK. Distinct subcellular localizations of Nox1 and Nox4 in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2004; 24: 677–683.[Abstract/Free Full Text]

25. Ambasta RK, Kumar P, Griendling KK, Schmidt HH, Busse R, Brandes RP. Direct interaction of the novel Nox proteins with p22phox is required for the formation of a functionally active NADPH oxidase. J Biol Chem. 2004; 279: 45935–45941.[Abstract/Free Full Text]

26. Seshiah PN, Weber DS, Rocic P, Valppu L, Taniyama Y, Griendling KK. Angiotensin II stimulation of NAD(P)H oxidase activity: upstream mediators. Circ Res. 2002; 91: 406–413.[Abstract/Free Full Text]

27. Touyz RM, Yao G, Schiffrin EL. c-Src induces phosphorylation and translocation of p47phox: role in superoxide generation by angiotensin II in human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2003; 23: 981–987.[Abstract/Free Full Text]

28. Takeya R, Ueno N, Kami K, Taura M, Kohjima M, Izaki T, Nunoi H, Sumimoto H. Novel human homologues of p47phox and p67phox participate in activation of superoxide-producing NADPH oxidases. J Biol Chem. 2003; 278: 25234–25246.[Abstract/Free Full Text]

29. Banfi B, Clark RA, Steger K, Krause KH. Two novel proteins activate superoxide generation by the NADPH oxidase NOX1. J Biol Chem. 2003; 278: 3510–3513.[Abstract/Free Full Text]

30. Li WG, Stoll LL, Rice JB, Xu SP, Miller FJ Jr, Chatterjee P, Hu L, Oberley LW, Spector AA, Weintraub NL. Activation of NAD(P)H oxidase by lipid hydroperoxides: mechanism of oxidant-mediated smooth muscle cytotoxicity. Free Radic Biol Med. 2003; 34: 937–946.[CrossRef][Medline] [Order article via Infotrieve]

31. Li WG, Miller FJ Jr, Zhang HJ, Spitz DR, Oberley LW, Weintraub NL. H(2)O(2)-induced O(2) production by a non-phagocytic NAD(P)H oxidase causes oxidant injury. J Biol Chem. 2001; 276: 29251–29256.[Abstract/Free Full Text]

32. Harrison R. Structure and function of xanthine oxidoreductase: where are we now? Free Radic Biol Med. 2002; 33: 774–797.[CrossRef][Medline] [Order article via Infotrieve]

33. Sakuma S, Fujimoto Y, Sakamoto Y, Uchiyama T, Yoshioka K, Nishida H, Fujita T. Peroxynitrite induces the conversion of xanthine dehydrogenase to oxidase in rabbit liver. Biochem Biophys Res Commun. 1997; 230: 476–479.[CrossRef][Medline] [Order article via Infotrieve]

34. Friedl HP, Till GO, Ryan US, Ward PA. Mediator-induced activation of xanthine oxidase in endothelial cells. FASEB J. 1989; 3: 2512–2518.[Abstract]

35. McNally JS, Davis ME, Giddens DP, Saha A, Hwang J, Dikalov S, Jo H, Harrison DG. Role of xanthine oxidoreductase and NAD(P)H oxidase in endothelial superoxide production in response to oscillatory shear stress. Am J Physiol Heart Circ Physiol. 2003; 285: H2290–H2297.[Abstract/Free Full Text]

36. Linder N, Rapola J, Raivio KO. Cellular expression of xanthine oxidoreductase protein in normal human tissues. Lab Invest. 1999; 79: 967–974.[Medline] [Order article via Infotrieve]

37. Guthikonda S, Sinkey C, Barenz T, Haynes WG. Xanthine oxidase inhibition reverses endothelial dysfunction in heavy smokers. Circulation. 2003; 107: 416–421.[Abstract/Free Full Text]

38. Cardillo C, Kilcoyne CM, Cannon RO 3rd, Quyyumi AA, Panza JA. Xanthine oxidase inhibition with oxypurinol improves endothelial vasodilator function in hypercholesterolemic but not in hypertensive patients. Hypertension. 1997; 30: 57–63.[Abstract/Free Full Text]

39. Farquharson CA, Butler R, Hill A, Belch JJ, Struthers AD. Allopurinol improves endothelial dysfunction in chronic heart failure. Circulation. 2002; 106: 221–226.[Abstract/Free Full Text]

40. Sohn HY, Krotz F, Gloe T, Keller M, Theisen K, Klauss V, Pohl U. Differential regulation of xanthine and NAD(P)H oxidase by hypoxia in human umbilical vein endothelial cells. Role of nitric oxide and adenosine. Cardiovasc Res. 2003; 58: 638–646.[Abstract/Free Full Text]

41. Fukushima T, Adachi T, Hirano K. The heparin-binding site of human xanthine oxidase. Biol Pharm Bull. 1995; 18: 156–158.[Medline] [Order article via Infotrieve]

42. Houston M, Estevez A, Chumley P, Aslan M, Marklund S, Parks DA, Freeman BA. Binding of xanthine oxidase to vascular endothelium. Kinetic characterization and oxidative impairment of nitric oxide-dependent signaling. J Biol Chem. 1999; 274: 4985–4994.[Abstract/Free Full Text]

43. Landmesser U, Spiekermann S, Dikalov S, Tatge H, Wilke R, Kohler C, Harrison DG, Hornig B, Drexler H. Vascular oxidative stress and endothelial dysfunction in patients with chronic heart failure: role of xanthine-oxidase and extracellular superoxide dismutase. Circulation. 2002; 106: 3073–3078.[Abstract/Free Full Text]

44. Vasquez-Vivar J, Kalyanaraman B, Martasek P, Hogg N, Masters BS, Karoui H, Tordo P, Pritchard KA Jr. Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc Natl Acad Sci U S A. 1998; 95: 9220–9225.[Abstract/Free Full Text]

45. Stroes E, Kastelein J, Cosentino F, Erkelens W, Wever R, Koomans H, Luscher T, Rabelink T. Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J Clin Invest. 1997; 99: 41–46.[Medline] [Order article via Infotrieve]

46. Landmesser U, Dikalov S, Price SR, McCann L, Fukai T, Holland SM, Mitch WE, Harrison DG. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest. 2003; 111: 1201–1209.[CrossRef][Medline] [Order article via Infotrieve]

47. Wallace DC. Mitochondrial diseases in man and mouse. Science. 1999; 283: 1482–1488.[Abstract/Free Full Text]

48. Turrens JF. Mitochondrial formation of reactive oxygen species. J Physiol. 2003; 552: 335–344.[Abstract/Free Full Text]

49. Ballinger SW, Patterson C, Yan CN, Doan R, Burow DL, Young CG, Yakes FM, Van Houten B, Ballinger CA, Freeman BA, Runge MS. Hydrogen peroxide- and peroxynitrite-induced mitochondrial DNA damage and dysfunction in vascular endothelial and smooth muscle cells. Circ Res. 2000; 86: 960–966.[Abstract/Free Full Text]

50. Ali MH, Pearlstein DP, Mathieu CE, Schumacker PT. Mitochondrial requirement for endothelial responses to cyclic strain: implications for mechanotransduction. Am J Physiol Lung Cell Mol Physiol. 2004; 287: L486–L496.[Abstract/Free Full Text]

51. Heitzer T, Wenzel U, Hink U, Krollner D, Skatchkov M, Stahl RA, MacHarzina R, Brasen JH, Meinertz T, Munzel T. Increased NAD(P)H oxidase-mediated superoxide production in renovascular hypertension: evidence for an involvement of protein kinase C. Kidney Int. 1999; 55: 252–260.[CrossRef][Medline] [Order article via Infotrieve]

52. Li N, Ragheb K, Lawler G, Sturgis J, Rajwa B, Melendez JA, Robinson JP. Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. J Biol Chem. 2003; 278: 8516–8525.[Abstract/Free Full Text]

53. Afanas Ev IB. Superoxide Ion Chemistry and Biological Implications. Boca Raton, Fla: CRC Press; 1989.

54. Tribble DL, Gong EL, Leeuwenburgh C, Heinecke JW, Carlson EL, Verstuyft JG, Epstein CJ. Fatty streak formation in fat-fed mice expressing human copper-zinc superoxide dismutase. Arterioscler Thromb Vasc Biol. 1997; 17: 1734–1740.[Abstract/Free Full Text]

55. Droge W. Free radicals in the physiological control of cell function. Physiol Rev. 2002; 82: 47–95.[Abstract/Free Full Text]

56. Matoba T, Shimokawa H, Kubota H, Morikawa K, Fujiki T, Kunihiro I, Mukai Y, Hirakawa Y, Takeshita A. Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in human mesenteric arteries. Biochem Biophys Res Commun. 2002; 290: 909–913.[CrossRef][Medline] [Order article via Infotrieve]

57. Matoba T, Shimokawa H, Nakashima M, Hirakawa Y, Mukai Y, Hirano K, Kanaide H, Takeshita A. Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice. J Clin Invest. 2000; 106: 1521–1530.[Medline] [Order article via Infotrieve]

58. Schmalhausen EV, Pleten AP, Muronetz VI. Ascorbate-induced oxidation of glyceraldehyde-3-phosphate dehydrogenase. Biochem Biophys Res Commun. 2003; 308: 492–496.[CrossRef][Medline] [Order article via Infotrieve]

59. Denu JM, Tanner KG. Redox regulation of protein tyrosine phosphatases by hydrogen peroxide: detecting sulfenic acid intermediates and examining reversible inactivation. Methods Enzymol. 2002; 348: 297–305.[Medline] [Order article via Infotrieve]

60. Peshenko IV, Shichi H. Oxidation of active center cysteine of bovine 1-Cys peroxiredoxin to the cysteine sulfenic acid form by peroxide and peroxynitrite. Free Radic Biol Med. 2001; 31: 292–303.[CrossRef][Medline] [Order article via Infotrieve]

61. Zheng L, Nukuna B, Brennan ML, Sun M, Goormastic M, Settle M, Schmitt D, Fu X, Thomson L, Fox PL, Ischiropoulos H, Smith JD, Kinter M, Hazen SL. Apolipoprotein A-I is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease. J Clin Invest. 2004; 114: 529–541.[CrossRef][Medline] [Order article via Infotrieve]

62. Laude K, Cai H, Fink B, Hoch N, Weber D, McCann L, Kojda G, Fukai T, Schmidt HH, Dikalov S, Ramasamy S, Gamez G, Griendling K, Harrison D. Hemodynamic and biochemical adaptations to vascular smooth muscle overexpression of p22phox in mice. Am J Physiol Heart Circ Physiol. In press.

63. Weber DS, Rocic P, Mellis AM, Laude K, Lyle AN, Harrison DG, Griendling KK. Angiotensin II-induced hypertrophy is potentiated in mice overexpressing p22phox in vascular smooth muscle. Am J Physiol Heart Circ Physiol. In press.

64. Khatri JJ, Johnson C, Magid R, Lessner SM, Laude KM, Dikalov SI, Harrison DG, Sung HJ, Rong Y, Galis ZS. Vascular oxidant stress enhances progression and angiogenesis of experimental atheroma. Circulation. 2004; 109: 520–525.[Abstract/Free Full Text]

Related Article:

ATVB In Focus: Redox Mechanisms in Blood Vessels

Kathy K. Griendling
Arterioscler Thromb Vasc Biol 2005 25: 272-273. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				X. Zhou, H. G. Bohlen, J. L. Unthank, and S. J. Miller Abnormal nitric oxide production in aged rat mesenteric arteries is mediated by NAD(P)H oxidase-derived peroxide Am J Physiol Heart Circ Physiol, December 1, 2009; 297(6): H2227 - H2233. [Abstract] [Full Text] [PDF]

				E. Yamamoto, K. Kataoka, Y.-F. Dong, T. Nakamura, M. Fukuda, Y. Tokutomi, S. Matsuba, H. Nako, N. Nakagata, T. Kaneko, et al. Aliskiren Enhances the Protective Effects of Valsartan Against Cardiovascular and Renal Injury in Endothelial Nitric Oxide Synthase-Deficient Mice Hypertension, September 1, 2009; 54(3): 633 - 638. [Abstract] [Full Text] [PDF]

				D. Graham, N. N. Huynh, C. A. Hamilton, E. Beattie, R. A.J. Smith, H. M. Cocheme, M. P. Murphy, and A. F. Dominiczak Mitochondria-Targeted Antioxidant MitoQ10 Improves Endothelial Function and Attenuates Cardiac Hypertrophy Hypertension, August 1, 2009; 54(2): 322 - 328. [Abstract] [Full Text] [PDF]

				R.-J. Teng, A. Eis, I. Bakhutashvili, N. Arul, and G. G. Konduri Increased superoxide production contributes to the impaired angiogenesis of fetal pulmonary arteries with in utero pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, July 1, 2009; 297(1): L184 - L195. [Abstract] [Full Text] [PDF]

				M. S. Wolin Reactive oxygen species and the control of vascular function Am J Physiol Heart Circ Physiol, March 1, 2009; 296(3): H539 - H549. [Abstract] [Full Text] [PDF]

				A. Qu, C. Jiang, M. Xu, Y. Zhang, Y. Zhu, Q. Xu, C. Zhang, and X. Wang PGC-1{alpha} attenuates neointimal formation via inhibition of vascular smooth muscle cell migration in the injured rat carotid artery Am J Physiol Cell Physiol, January 1, 2009; 297(3): C645 - C653. [Abstract] [Full Text] [PDF]

				R. H. Fabian, J. R. Perez-Polo, and T. A. Kent Perivascular nitric oxide and superoxide in neonatal cerebral hypoxia-ischemia Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1809 - H1814. [Abstract] [Full Text] [PDF]

				E. Yamamoto, Y.-F. Dong, K. Kataoka, T. Yamashita, Y. Tokutomi, S. Matsuba, H. Ichijo, H. Ogawa, and S. Kim-Mitsuyama Olmesartan Prevents Cardiovascular Injury and Hepatic Steatosis in Obesity and Diabetes, Accompanied by Apoptosis Signal Regulating Kinase-1 Inhibition Hypertension, September 1, 2008; 52(3): 573 - 580. [Abstract] [Full Text] [PDF]

				A.-L. Levonen, E. Vahakangas, J. K. Koponen, and S. Yla-Herttuala Antioxidant Gene Therapy for Cardiovascular Disease: Current Status and Future Perspectives Circulation, April 22, 2008; 117(16): 2142 - 2150. [Abstract] [Full Text] [PDF]

				B. C. Berk Atheroprotective Signaling Mechanisms Activated by Steady Laminar Flow in Endothelial Cells Circulation, February 26, 2008; 117(8): 1082 - 1089. [Full Text] [PDF]

				Y.-H. Du, Y.-Y. Guan, N. J. Alp, K. M. Channon, and A. F. Chen Endothelium-Specific GTP Cyclohydrolase I Overexpression Attenuates Blood Pressure Progression in Salt-Sensitive Low-Renin Hypertension Circulation, February 26, 2008; 117(8): 1045 - 1054. [Abstract] [Full Text] [PDF]

				S. Heumuller, S. Wind, E. Barbosa-Sicard, H. H.H.W. Schmidt, R. Busse, K. Schroder, and R. P. Brandes Apocynin Is Not an Inhibitor of Vascular NADPH Oxidases but an Antioxidant Hypertension, February 1, 2008; 51(2): 211 - 217. [Abstract] [Full Text] [PDF]

				T. Nakamura, E. Yamamoto, K. Kataoka, T. Yamashita, Y. Tokutomi, Y.-F. Dong, S. Matsuba, H. Ogawa, and S. Kim-Mitsuyama Beneficial Effects of Pioglitazone on Hypertensive Cardiovascular Injury Are Enhanced by Combination With Candesartan Hypertension, February 1, 2008; 51(2): 296 - 301. [Abstract] [Full Text] [PDF]

				T. M. Paravicini and R. M. Touyz NADPH Oxidases, Reactive Oxygen Species, and Hypertension: Clinical implications and therapeutic possibilities Diabetes Care, February 1, 2008; 31(Supplement_2): S170 - S180. [Abstract] [Full Text] [PDF]

				E. Yamamoto, K. Kataoka, H. Shintaku, T. Yamashita, Y. Tokutomi, Y.-F. Dong, S. Matsuba, H. Ichijo, H. Ogawa, and S. Kim-Mitsuyama Novel Mechanism and Role of Angiotensin II Induced Vascular Endothelial Injury in Hypertensive Diastolic Heart Failure Arterioscler Thromb Vasc Biol, December 1, 2007; 27(12): 2569 - 2575. [Abstract] [Full Text] [PDF]

				C. Wadham, A. Parker, L. Wang, and P. Xia High Glucose Attenuates Protein S-Nitrosylation in Endothelial Cells: Role of Oxidative Stress Diabetes, November 1, 2007; 56(11): 2715 - 2721. [Abstract] [Full Text] [PDF]

				T. Nakamura, E. Yamamoto, K. Kataoka, T. Yamashita, Y. Tokutomi, Y.-F. Dong, S. Matsuba, H. Ogawa, and S. Kim-Mitsuyama Pioglitazone Exerts Protective Effects Against Stroke in Stroke-Prone Spontaneously Hypertensive Rats, Independently of Blood Pressure Stroke, November 1, 2007; 38(11): 3016 - 3022. [Abstract] [Full Text] [PDF]

				T. Yamashita, E. Yamamoto, K. Kataoka, T. Nakamura, S. Matsuba, Y. Tokutomi, Y.-F. Dong, H. Ichijo, H. Ogawa, and S. Kim-Mitsuyama Apoptosis Signal-Regulating Kinase-1 Is Involved in Vascular Endothelial and Cardiac Remodeling Caused by Nitric Oxide Deficiency Hypertension, September 1, 2007; 50(3): 519 - 524. [Abstract] [Full Text] [PDF]

				S. Selemidis, G. J. Dusting, H. Peshavariya, B. K. Kemp-Harper, and G. R. Drummond Nitric oxide suppresses NADPH oxidase-dependent superoxide production by S-nitrosylation in human endothelial cells Cardiovasc Res, July 15, 2007; 75(2): 349 - 358. [Abstract] [Full Text] [PDF]

				H.-J. Sung, A. Yee, S. G. Eskin, and L. V. McIntire Cyclic strain and motion control produce opposite oxidative responses in two human endothelial cell types Am J Physiol Cell Physiol, July 1, 2007; 293(1): C87 - C94. [Abstract] [Full Text] [PDF]

				A. Fukatsu, T. Hayashi, A. Miyazaki-Akita, H. Matsui-Hirai, Y. Furutate, A. Ishitsuka, Y. Hattori, and A. Iguchi Possible usefulness of apocynin, an NADPH oxidase inhibitor, for nitrate tolerance: prevention of NO donor-induced endothelial cell abnormalities Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H790 - H797. [Abstract] [Full Text] [PDF]

				G. Gavazzi, C. Deffert, C. Trocme, M. Schappi, F. R. Herrmann, and K.-H. Krause NOX1 Deficiency Protects From Aortic Dissection in Response to Angiotensin II Hypertension, July 1, 2007; 50(1): 189 - 196. [Abstract] [Full Text] [PDF]

				D. X. Zhang and D. D. Gutterman Mitochondrial reactive oxygen species-mediated signaling in endothelial cells Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2023 - H2031. [Abstract] [Full Text] [PDF]

				E. Yamamoto, T. Yamashita, T. Tanaka, K. Kataoka, Y. Tokutomi, Z.-F. Lai, Y.-F. Dong, S. Matsuba, H. Ogawa, and S. Kim-Mitsuyama Pravastatin Enhances Beneficial Effects of Olmesartan on Vascular Injury of Salt-Sensitive Hypertensive Rats, via Pleiotropic Effects Arterioscler Thromb Vasc Biol, March 1, 2007; 27(3): 556 - 563. [Abstract] [Full Text] [PDF]

				I. Papparella, G. Ceolotto, L. Berto, M. Cavalli, S. Bova, G. Cargnelli, E. Ruga, O. Milanesi, L. Franco, M. Mazzoni, et al. Vitamin C prevents zidovudine-induced NAD(P)H oxidase activation and hypertension in the rat Cardiovasc Res, January 15, 2007; 73(2): 432 - 438. [Abstract] [Full Text] [PDF]

				T. Szasz, K. Thakali, G. D. Fink, and S. W. Watts A Comparison of Arteries and Veins in Oxidative Stress: Producers, Destroyers, Function, and Disease Experimental Biology and Medicine, January 1, 2007; 232(1): 27 - 37. [Abstract] [Full Text] [PDF]

				K. Bedard and K.-H. Krause The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology Physiol Rev, January 1, 2007; 87(1): 245 - 313. [Abstract] [Full Text] [PDF]

				I. Chinen, M. Shimabukuro, K. Yamakawa, N. Higa, T. Matsuzaki, K. Noguchi, S. Ueda, M. Sakanashi, and N. Takasu Vascular Lipotoxicity: Endothelial Dysfunction via Fatty-Acid-Induced Reactive Oxygen Species Overproduction in Obese Zucker Diabetic Fatty Rats Endocrinology, January 1, 2007; 148(1): 160 - 165. [Abstract] [Full Text] [PDF]

				R. M. Weiss, M. Ohashi, J. D. Miller, S. G. Young, and D. D. Heistad Calcific Aortic Valve Stenosis in Old Hypercholesterolemic Mice Circulation, November 7, 2006; 114(19): 2065 - 2069. [Abstract] [Full Text] [PDF]

				S. Dayal, K. M. Wilson, L. Leo, E. Arning, T. Bottiglieri, and S. R. Lentz Enhanced susceptibility to arterial thrombosis in a murine model of hyperhomocysteinemia Blood, October 1, 2006; 108(7): 2237 - 2243. [Abstract] [Full Text] [PDF]

				F. M. Faraci Hydrogen peroxide: watery fuel for change in vascular biology. Arterioscler Thromb Vasc Biol, September 1, 2006; 26(9): 1931 - 1933. [Full Text] [PDF]

				A. Kontush and M. J. Chapman Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis Pharmacol. Rev., September 1, 2006; 58(3): 342 - 374. [Abstract] [Full Text] [PDF]

				H. Li, K. Witte, M. August, I. Brausch, U. Godtel-Armbrust, A. Habermeier, E. I. Closs, M. Oelze, T. Munzel, and U. Forstermann Reversal of Endothelial Nitric Oxide Synthase Uncoupling and Up-Regulation of Endothelial Nitric Oxide Synthase Expression Lowers Blood Pressure in Hypertensive Rats J. Am. Coll. Cardiol., June 20, 2006; 47(12): 2536 - 2544. [Abstract] [Full Text] [PDF]

				F. M. Faraci, M. L. Modrick, C. M. Lynch, L. A. Didion, P. E. Fegan, and S. P. Didion Selective cerebral vascular dysfunction in Mn-SOD-deficient mice J Appl Physiol, June 1, 2006; 100(6): 2089 - 2093. [Abstract] [Full Text] [PDF]

				S Moncada Adventures in vascular biology: a tale of two mediators Phil Trans R Soc B, May 29, 2006; 361(1469): 735 - 759. [Abstract] [Full Text] [PDF]

				D. D. Heistad Oxidative Stress and Vascular Disease: 2005 Duff Lecture Arterioscler Thromb Vasc Biol, April 1, 2006; 26(4): 689 - 695. [Abstract] [Full Text] [PDF]

				S. M. Bode-Boger, F. Scalera, J. T. Kielstein, J. Martens-Lobenhoffer, G. Breithardt, M. Fobker, and H. Reinecke Symmetrical Dimethylarginine: A New Combined Parameter for Renal Function and Extent of Coronary Artery Disease J. Am. Soc. Nephrol., April 1, 2006; 17(4): 1128 - 1134. [Abstract] [Full Text] [PDF]

				F. M. Faraci Reactive oxygen species: influence on cerebral vascular tone J Appl Physiol, February 1, 2006; 100(2): 739 - 743. [Abstract] [Full Text] [PDF]

				R. W. Alexander Leukocyte and Endothelial Angiotensin II Type 1 Receptors and Microvascular Thrombotic and Inflammatory Responses to Hypercholesterolemia Arterioscler Thromb Vasc Biol, February 1, 2006; 26(2): 240 - 241. [Full Text] [PDF]

				O. A. Hatoum, M. F. Otterson, D. Kopelman, H. Miura, I. Sukhotnik, B. T. Larsen, R. M. Selle, J. E. Moulder, and D. D. Gutterman Radiation Induces Endothelial Dysfunction in Murine Intestinal Arterioles via Enhanced Production of Reactive Oxygen Species Arterioscler Thromb Vasc Biol, February 1, 2006; 26(2): 287 - 294. [Abstract] [Full Text] [PDF]

				P. Sjogren, S. Basu, M. Rosell, A. Silveira, U. de Faire, B. Vessby, A. Hamsten, M.-L. Hellenius, and R. M. Fisher Measures of Oxidized Low-Density Lipoprotein and Oxidative Stress Are Not Related and Not Elevated in Otherwise Healthy Men With the Metabolic Syndrome Arterioscler Thromb Vasc Biol, December 1, 2005; 25(12): 2580 - 2586. [Abstract] [Full Text] [PDF]

				M. S. Wolin Loss of Vascular Regulation by Soluble Guanylate Cyclase Is Emerging as a Key Target of the Hypertensive Disease Process Hypertension, June 1, 2005; 45(6): 1068 - 1069. [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 25/2/274    most recent 01.ATV.0000149143.04821.ebv1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mueller, C. F.H. Articles by Harrison, D. G. Search for Related Content PubMed PubMed Citation Articles by Mueller, C. F.H. Articles by Harrison, D. G. Related Collections Redox Mechanisms in Blood Vessels Related Article