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Cardiovascular Research 2005 65(1):16-27; doi:10.1016/j.cardiores.2004.08.007
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Copyright © 2004, European Society of Cardiology

Vascular NADPH oxidases: molecular mechanisms of activation

Ralf P. Brandes* and Jörg Kreuzer

Institut für Kardiovaskuläre Physiologie, Universität Frankfurt, Frankfurt, Germany
Innere Medizin III, Universität Heidelberg, Heidelberg, Germany

* Corresponding author. Institut für Kardiovaskuläre Physiologie, Klinikum der J.W. Goethe-Universität, Theodor-Stern-Kai 7, D-60596 Frankfurt am Main, Germany. Tel.: +49 69 6301 6995; fax: +49 69 6301 7668. Email address: r.brandes{at}em.uni-frankfurt.de

Received 17 June 2004; revised 8 August 2004; accepted 9 August 2004


   Abstract
Top
 Abstract
1. Introduction
 2. Structural components of...
 3. Assembly of NADPH...
 4. Upstream signalling and...
 5. Vascular NADPH oxidases
 6. Conclusion
 References
 
Oxygen-derived free radicals are thought to contribute to the initiation and progression of cardiovascular disease via several different mechanisms, such as consumption of nitric oxide, oxidation of proteins and lipids, and activation of redox-sensitive signalling cascades. Vascular NADPH oxidases are important sources of vascular radical formation. The activities of these enzymes, which in some aspects are similar to the leukocyte NADPH oxidase, are controlled on the expression level and complex activation mechanisms. As a plethora of vascular stimuli, such as growth factors, cytokines, physical stimuli, and lipids elicits radical formation by these enzymes, a careful analysis is required for the understanding of the activation of the NADPH oxidases. This article reviews the components of the NADPH oxidases in leukocytes and vascular tissue. Emphasis is put on the activation of the oxidases, including upstream signalling events and molecular modes of interaction between the subunits.

KEYWORDS NADPH oxidase; p22phox; Oxygen-derived free radicals; Nox


   1. Introduction
Top
 Abstract
 1. Introduction
2. Structural components of...
 3. Assembly of NADPH...
 4. Upstream signalling and...
 5. Vascular NADPH oxidases
 6. Conclusion
 References
 
Reactive oxygen species (ROS) decisively contribute to cellular signalling, affecting almost all aspects of cellular function including gene expression, proliferation, migration, and cell death.

In the vasculature, several differentially localized and expressed enzyme systems contribute to ROS formation, including endothelial NO synthases, enzymes of the respiratory chain, cytochrome P450 monoxygenases, xanthine oxidase, and NADPH oxidases. Although all of these enzymes contribute to the oxidative burden, evidence is accumulating that an initial generation of ROS by NADPH oxidases triggers the release of ROS by the other enzymes [1]. Consequently, the vascular NADPH oxidases have been suggest to have a role for the development of hypertension, endothelial dysfunction, arteriosclerosis, restenosis, and hypertrophy [2].

Originally described as a basally active enzyme, which can be stimulated with angiotensin II (AngII; [3]), it is now clear that a multitude of compounds, including growth factors [4,5], cytokines [6], mechanical forces [7], and lipids [8], elicit radical formation via an induction and/or activation of vascular NADPH oxidases. Moreover, with the discovery of homologues to several subunits of the classic leukocyte-type NADPH oxidase [9], it becomes important to understand the modes of activation of the different NADPH oxidase isoforms expressed in the vasculature and how they contribute to oxidative stress and cardiovascular physiology and pathology.

In this review, after a brief introduction to the structural component of the NADPH oxidases, we focus on the different signalling pathways involved in the activation of NADPH oxidases.


   2. Structural components of NADPH oxidases
Top
 Abstract
 1. Introduction
 2. Structural components of...
3. Assembly of NADPH...
 4. Upstream signalling and...
 5. Vascular NADPH oxidases
 6. Conclusion
 References
 
2.1. The leukocyte NADPH oxidase
The classic NADPH oxidase, which is expressed predominantly in polymorph-nuclear neutrophils (PMN), has a central role in the host defence and is involved in bacteria killing PMN. The enzyme consists of two membrane-bound subunits, a 91-kDa protein gp91phox and the 22-kDa p22phox and at least three cytoplasmic subunits. The glycoprotein gp91phox, which is now also termed Nox 2, has six membrane-spanning domains, carries two hemes, and contains the NADPH binding site. Nox 2 interacts with p22phox to form a cytochrome b558 complex, and this interaction is required for oxidase activity. Activation of PMN (discussed below) leads to a translocation of the small GTPase Rac2, and of p47phox and p67phox to the plasma membrane where p67phox interacts via its activation domain with the membrane-bound subunits. This interaction is required for oxidase activation and facilitates the transfer of electrons from NADPH to oxygen (for a detailed review, see Ref. [10]). Two further proteins have been demonstrated to interact with the cytochrome b558 complex: Rap1a and p40phox, the latter being involved in membrane recruitment of p67phox and p47phox [11].

2.2. Gp91phox homologues
Starting with the identification of the Nox1 [12] and Nox4 [13], a family of gp91phox homologues was discovered, which has to date seven members. This new enzyme family is structured into three main groups, according to the presence of specific domains [14]. The vascular expression of all Nox homologues appears to be low. Nox1 is primarily expressed in epithelial cells of the digestive tract [12], gp91phox, now termed Nox2, is highly expressed in PMN, Nox3 is found in the inner ear and is required for otoconia formation [15], and Nox4 [13], formerly known as Renox is mostly expressed in the kidney. These four homologues are characterized by their calcium-independency. In contrast, the activity of Nox5, which is mostly expressed in spermatozoae and lymphocytes is increased by calcium [16]. Different to these two groups, a third group of enzymes has been identified, which carries an additional peroxidase domain and is termed dual-oxidase Duox [17], exhibiting high expression in the thyroid gland (Duox 1 and 2), prostate, lung (Duox 1), and the intestine (Duox 2; [18]).

2.3. Homologues to cytoplasmic subunits
There are also homologues to the cytoplasmic components p47phox and p67phox of the leukocyte oxidase, which are termed NoxO1 and NoxA1 respectively [19–21]. These homologues appear to exhibit a similar tissue distribution as Nox1 and are therefore considered to be involved in Nox1 activation. Finally, the expression of the small GTPase Rac2 is restricted to leukocytes, but the Rac1 is expressed ubiquitously and can substitute Rac2.


   3. Assembly of NADPH oxidases
Top
 Abstract
 1. Introduction
 2. Structural components of...
 3. Assembly of NADPH...
4. Upstream signalling and...
 5. Vascular NADPH oxidases
 6. Conclusion
 References
 
3.1. Assembly of the leukocyte NADPH oxidase
The leukocyte NADPH oxidase is inactive under resting conditions. Several different agonists, such as fMLP and opsonized zymosan, the latter via the antibody Fc fragment, activate the oxidase in leukocytes, resulting in a massive generation of O2– (approximately 10 nmol/min/106 cells). Under physiological conditions, this is a highly controlled process which requires three different elements, and several models exist regarding the very exact protein–protein interaction occurring in the assembled NADPH oxidase [22]. Nevertheless, it is certain that the cytoplasmic subunit p67phox has to interact with gp91phox [23,24], that active Rac is required for oxidase activity [25], and that–at least in vivo–free fatty acids have to be present [26,27].

The activation of gp91phox by p67phox occurs via an activation domain located in the N-terminal part of p67phox. The interaction at this site however is not strong enough to allow steady association of the two molecules and is rather facilitated by p47phox, which acts as adaptor protein. This function of p47phox is governed by serine phosphorylation, which occurs during activation of the oxidase [28]. Nonphosphorylated p47phox does not interact with the membrane and other oxidase subunits, as the interacting SH3 domains and the PX domain are covered by an autoinhibitory loop [29]. Serine phosphorylation at the positions 303, 304, and 328 results in a conformational change of p47phox and the exposure of the interacting domains [29]. The bis-SH3-domain of p47phox has been suggested to bind p22phox [29,30], whereas the PX domain allows anchoring of p47phox in the membrane [31]. P67phox is thought to interact via its SH3 domain with the proline-rich region in p47phox [32]. Consequently, p22phox is considered to be the primary docking site for the cytosolic components. Moreover, p22phox stabilizes gp91phox and is required for the processing of the larger subunit through the cell [33].

The small GTPase Rac is also critical for oxidase activation. Rac-GTP interacts with the oxidase via the TPR motif in the N-terminal part of p67phox [34]. Membrane binding of Rac does not require p47phox, as active Rac anchors in the membrane via its prenylated tail. Indeed, high amounts of Rac have been shown to track p67phox to the membrane even in the absence of p47phox [35]. In vivo, the translocation of Rac is independent of that of p47phox, and p67phox and still takes place in patients lacking NADPH oxidase expression[36] (Fig. 1).


Figure 1
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  		Fig. 1 Assembly of the leukocyte NADPH oxidase. (A) At resting state, Rac exists in an inactive GDP-bound form with the geranylgeranyl-tail bound to GDI. p47phox (p47) is inactive via the autoinhibitory region (AIR) covering the interaction domains. Activation occurs by GDP–GTP exchange at Rac and serine phosphorylation of p47phox, which leads to the release of the AIR. (B) Free Rac-GTP interacts with the tetratricopeptide repeat (TRP) motive of p67phox. The PX domain of p47phox interacts with the plasma membrane, the SH3 domains in p47phox interact with p22phox, whereas the proline-rich (PR) region interacts with the SH3 domain in p67phox (p67). (C) These interactions lead to the approximation of the activation domain (AD) of p67phox to the activation side (AS) in gp91phox and therefore to oxidase activation. It is uncertain whether Rac only interacts with p67phox or whether also a direct interaction with gp91phox occurs.

 
3.2. Assembly of NADPH oxidases homologues
Almost nothing has been published on the assembly and activation of Nox1, Nox3, and Nox4 containing NADPH oxidases. Nox1 and Nox4, similar to gp91phox, form complexes with p22phox [37], and p22phox is required for Nox1-dependent O2– formation [21].

The functional differences of the cytoplasmic homologues NoxO1 and NoxA1 as compared to the p47phox and p67phox proteins are incompletely understood. The lack of the autoinhibitory loop in the p47phox homologue NoxO1 however suggests a constitutive, or at least increased basal, activity of NoxO1-containing NADPH oxidases. Indeed, different to p47phox, where the PX and SH3 domains are usually covered by the autoinhibitory loop, the binding domains of NoxO1 are freely accessible, and this leads to membrane association and interaction of this subunit with Nox1 already at resting state [38]. Consequently, NoxO1-carrying NADPH oxidase elicits high constitutive O2– production [19,20]. It appears that the activity of this complex cannot be further enhanced by known stimuli of the classic gp91phox-containing NADPH oxidase, such as phorbol ester, but this observation, which might be influenced by the species and host cell studied, requires further confirmation [19–21]. Although it is likely that a large part of the regulation of the Nox1–NoxO1–NoxA1 complex activity occurs at the transcriptional level [39], the role of Rac in Nox1 activation has not been extensively studied so far. Very recently, it was suggested that activation of Rac1 in Caco-2 and HEK293 cells by a direct interaction with Nox1 increases ROS production in response to epidermal growth factor (EGF; [40]). Further studies are needed to substantiate this finding as a direct interaction of Rac with membrane-bound Nox proteins is still controversial.

Little is known regarding the assembly of the Nox4-containing NADPH oxidase. Nox4 forms stable complexes with p22phox [37]. Coexpression of Nox4 together with p47phox and p67phox however does not increase cellular ROS generation [41,42], and also coexpression of NoxO1 and NoxA1 had no effect on Nox4-dependent ROS formation[37]. The data regarding a possible activation of Nox4 by Rac and fatty acids are controversial [41,43], which might be influenced by the assay systems and cell types studied. The activation of Nox4 particular in vascular cells is completely uncertain, and the few studies discussing this aspect assume a constitutive activity of Nox4-containing NADPH oxidase [42,44,45]. To date, no study has addressed the importance of NoxO1 and NoxA1 for vascular radical generation.


   4. Upstream signalling and activation of the leukocyte NADPH oxidases
Top
 Abstract
 1. Introduction
 2. Structural components of...
 3. Assembly of NADPH...
 4. Upstream signalling and...
5. Vascular NADPH oxidases
 6. Conclusion
 References
 
Activation of the leukocyte NADPH oxidase can occur via different signalling pathways. Tyrosine kinase receptors, such as the receptor for the Fc fragment, are involved in leukocyte activation in response to opsonized stimuli [46], whereas G-protein-coupled receptors mediate the response to the classic chemoattractant fMLP [47]. Phorbol ester is frequently used to pharmacologically activate the oxidase. The final passage of all these stimuli is the phosphorylation of p47phox, the activation of Rac, and the release of free fatty acids, which then leads to oxidase assembly, as discussed above, whereas the upstream signalling varies considerably. Phorbol esters, mimicking the action of diacylglycerol, are strong activators of protein kinase C (PKC; [48]). They also strongly activate Rac, by a putative PKC-independent mechanism [48], as they directly activate the Ras-guanine nucleotide exchange factor (GEF) Ras-GRP, and several Rac-GTPase activating proteins (GAPs) [49]. Phorbol esters elicit a robust long-lasting activation of the NADPH oxidase. In contrast to this, fMLP, which activates the oxidase via stimulation of an inhibitory G-protein (Gi), involving a different signal transduction cascade, yields only a transient release of O2– [50]. Gi activates the leukocyte phosphoinositol-3-kinase (PI3-K). Among the different PI3-K isoforms, type {alpha}, β, and {delta} are activated by tyrosine kinases, whereas PI3-K{gamma} is activated via G-protein-dependent mechanism [51]. The isoforms {delta} and {gamma} are preferentially expressed in the leukocytes, and PI3-K{gamma} is the one involved in fMLP signalling, whereas PI3-K{delta} may mediate the activation of the oxidase in response to ligands at the tyrosine kinase receptor, such as opsonized zymosan [46]. The G-protein-mediated activation of PI3-K occurs via a complex pathway involving MAP kinases [52]. PI3-K phosphorylates membrane lipids leading to the accumulation of phosphatidyl-inositol-triphosphate (PIP3; [53]), which is a crucial step in oxidase activation, and blockade of PI3-K inhibits O2– release in response to fMLP [54]. The PI3-K product PIP3 interacts with pleckstrin homology domains (PH) on proteins [55] and activates the serine kinase Akt/protein kinase B [55]. Akt phosphorylates p47phox on the serine residues required to release the autoinhibitory loop [56]. Moreover, PIP3 leads to GDP/GTP exchange at Rac, resulting in Rac activation [57]. In resting cells, the small GTPase Rac is present in an inactive form, binding GDP and forming a complex with a member of the guanine nucleotide dissociation inhibitor (GDI) family via its geranylgeranylated tail. Following dissociation from GDI, GEFs activate Rac by permitting GDP/GTP exchange, and activated Rac-GTP interacts with the membrane via its geranylgeranylated tail [58]. Several Rac GEFs are expressed in leukocytes. GEF-mediated activation of Rac can occur by Vav, Tiam, PIX, Ras-GRF, Sos, and other [59]. Some of them, in particular the GEF pRex [57] and Vav [60], are involved in oxidase activation and are PIP3-dependent [57]. Membrane-bound-activated Rac interacts with p67phox, a necessary step in oxidase activation. Interestingly, constitutively active Rac increases NADPH oxidase activity and p47phox translocation even in the absence of other stimuli, suggesting that by some means Rac facilitates phosphorylation of p47phox [61]. This observation indicates that kinases located downstream of Rac, such as p21-activated kinases (PAKs), can phosphorylate p47phox. Indeed, PAK is expressed in large abundance in leukocytes [62], and p47phox has been shown to be phosphorylated by PAK at several sites[63] (Fig. 2).


Figure 2
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  		Fig. 2 Receptor-mediated activation of the leukocyte NADPH oxidase. Stimulation of leukocytes with the peptide fMLP leads to the activation of a heptahelical receptor and dissociation of an inhibitory heterotrimeric G-protein. The activated Gi via several steps activates the phospholipase A2 (PLA2), leading to the release of arachidonic acid and activates the phophatidyl-inositol-3-kinase (PI3K). PI3K activity results in the accumulation of phosphotidyl-inositol-triphosphophate (PIP3), which activates Akt and PIP3-dependent GEFs. Akt serine phosphorylates p47phox. The activated GEF stimulates GDP–GTP exchange at Rac. Rac then can activate p67phox, interacts with the membrane but also activates p21-activated kinase (PAK). PAK, similar as Akt and protein kinase C (PKC), can serine phosphorylate p47phox and therefore activate it.

 

   5. Vascular NADPH oxidases
Top
 Abstract
 1. Introduction
 2. Structural components of...
 3. Assembly of NADPH...
 4. Upstream signalling and...
 5. Vascular NADPH oxidases
6. Conclusion
 References
 
5.1. Vascular expression profile of the NADPH oxidases
In leukocyte, the predominant NADPH oxidase is the gp91phox/Nox2-containing isoform. In vessels, the situation is completely different and very complex. Each of the vascular layers appears to have a particular composition of NADPH oxidases, which may even vary between species (for review, see Ref. [64]). The minimal conclusion with respect to the membrane-bound subunits from a large number of studies might be that p22phox [44,65,66] and Nox4 [42,44,66–68] are expressed in all vascular cells, whereas gp91phox expression predominates in the endothelium [65] and the adventitial [69] in conduit vessels. The vascular expression of Nox1 is low [12,44,66], and a role for Nox1 for vascular O2– generation has mainly been demonstrated in vascular smooth muscle cells (VSMC; [45]). With respect to the cytoplasmic subunits, Rac1 and p47phox have been observed in all vascular layers [64], whereas p67phox was only found in the endothelium [70] and adventitia [71], but not in the smooth muscle layer [72]. It remains to be determined whether a homologue to p67phox, such as NoxA1, replaces p67phox in VSMC. NoxA1 is detectable by real-time PCR in VSMC, but the mRNA expression is about 1000 times less (10 CT values) than that in colon cells (Brandes, RP and Schreiber, JG, unpublished observation 2004).

5.2. Activation of the vascular NADPH oxidase
As a consequence of the heterogeneity in vascular NADPH oxidase expression, the radical generation in response to identical stimuli may vary between cell types, and it remains often unclear which of the Nox homologues become activated and whether the mechanism of activation differ between the Nox homologues.

5.2.1. Growth factors signalling via G-protein-coupled receptors
A large number of activators of G-protein-coupled receptors activate NADPH oxidases. The characterization of the mechanism of action of the oxidase is most complete for angiotensin II [4]; however, thrombin has been shown to elicit similar responses [5,72,73]. Moreover, activation of the oxidases has been suggested to occur by catecholamines [74], histamine [75], serotonin [76], and prostaglandins [77].

5.2.1.1. Angiotensin II
Angiotensin II (AngII) is the paradigm for oxidase activation in the vasculature. It was the first compound discovered to increase NADPH oxidase activity in VSMC [3], and a vast number of studies aiming at the demonstration of an in vivo function of NADPH oxidases used AngII as stimulus for vascular superoxide generation [78]. AngII-mediated NADPH oxidase activation occurs via the action of the AT-1 receptor, whereas the AT-2 receptor appears to inhibit oxidase activation [79].

AngII signals via Gq/11 and Gi [80], which both may activate Rac. Following the action of the AT-1 receptor, AngII affects a multitude of different signalling cascades, eliciting the activation of PLA2 [81], PI3-K [82], phospholipase C and D, and PKC, as well as an increase in intracellular calcium [83]. Moreover, AngII stimulates leukotrien B4 (LTB4) production in VSMC, and inhibition of LTB4 attenuates ROS formation [84]. Indeed, arachidonic acid metabolites are involved in AngII-induced NADPH oxidase activation in rat aortic VSMC [85].

For AngII, a model of biphasic superoxide formation was proposed [4]. An initial activation of NADPH oxidase occurs via the action of PKC, whereas at later time points, the action of Src, EGF receptor transactivation, and subsequent activation of PI3-K leads to robust activation of Rac and an enhanced and prolonged oxidase-dependent ROS generation [4]. The second phase of NADPH oxidase activation appears to be PKC-independent as the initial AngII-mediated activation of Rac also stimulates PAK-1 activity [86], PAK-1 can substitute PKC as kinase for p47phox [63]. Rac activation in response to AngII occurs via two independent pathways; following AT1-receptor stimulation, Rac becomes activated within seconds by pathways sensitive to PKC inhibitors and tyrosine kinase inhibitors [86], which probably involve so far undefined GEFs. The subsequent Rac-dependent activation of the NADPH oxidase leads to formation of O2–, which activates Src [87] and then via the EGF receptor Rac. Stimulation of endothelial cells [88] and VSMC [89] with AngII has been shown to result in translocation and phosphorylation of p47phox, and also in this process the tyrosine kinase Src is involved [90] (Fig. 3).


Figure 3
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  		Fig. 3 Activation of the NADPH oxidase in vascular smooth muscle cells by angiotensin II. Angiotensin II binds the G-protein-coupled AT1 receptor, which, potentially via the action of the β/{gamma} subunit, leads to the activation of phospholipase C. The subsequent release of diacylglycerol activates protein kinase C, which phosphorylates p47phox. The AT1 receptor also activates Src. Via Src-mediated phosphorylation of phospholipase D (PLD), phosphatidic acid (PA) is release, which, in addition to arachidonic acid (AA) released due to the increase in intracellular calcium, has been implicated in oxidase activation. AA is metabolized by lipoxygenases (LOX) to leukotrienes (LT), other potential lipid activator of the oxidase. Src also phosphorylates the epidermal growth factor (EGF) receptor, a step suggested being involved in PI3-kinase activation. O2– generated from the NADPH oxidase per se may activate PKC and H2O2, the dismutation product of O2– is thought to activate Src and to induce EGF receptor phosphorylation.

 
This complex interplay of several signalling pathways puts the NADPH oxidase upstream and downstream of Src and the EGF receptor in a sense of a self-enforcing loop. That such a positive feedback mechanism is indeed functional is supported by the observation that exogenously-applied H2O2 can increase NADPH oxidase activity in fibroblasts and VSMC [91].

Different to the AT-1 receptor, the action of AngII on the AT-2 receptor inhibits oxidase activity, and this might be a consequence of the activation of protein tyrosine phosphatases, in particular of SHP-1 [79].

5.2.1.2. Thrombin
The mechanism of acitivation of the NADPH oxidase by thrombin appears to be similar to that reported for angiotensin II, it requires p47phox [73] and is associated with p47phox translocation [72]. Moreover, thrombin-mediated p38 MAP kinase activation is NADPH oxidase-dependent [5] and this process involves EGF receptor transactivation [92].

5.2.2. Agonists on tyrosine kinase receptors
The tyrosine kinase receptor agonist platelet-derived growth factor (PDGF) is known to increase ROS generation in VSMC [93] and fibroblasts [94]. In VSMC, PDGF-induced ROS formation is mediated by NADPH oxidases and depends on Rac1 [95], p22phox [96], p47phox [97], and Nox1 [45]. Although signalling of PDGF through the PDGF {alpha} and PDGF β receptor overlaps considerably [98], several reports exist regarding differences in ROS generation in response to stimulation with PDGF. Marumo et al. [93] observed that only PDGF-BB, via activating the PDGF β receptor, stimulates ROS production in human VSMC using the cytochrome C assay, whereas our data demonstrated that PDGF AA, which signals through the PDGF {alpha} receptor but not PDGF BB, increases ROS production in VSMCs using an H2O2 assay in membrane fragments and DCHF fluorescence, which detects intracellular peroxides [99]. The most likely explanation for these contrasting observations is the differences in the kinetic of ROS production. Activation of the PDGF {alpha} receptors leads to a rapid but transient release of ROS for only a few minutes [96], whereas stimulation of the PDGF β receptor peaks 30 min after stimulation [100]. Different to the G-protein-coupled AT1 receptor, the PDGF receptors are tyrosine kinase receptors, which directly interact with PI3-K, SHP-2, GAP, and phospholipase C. Using mutants of the PDGF β receptor, it was shown that only the interaction with PI3-K was required to increase ROS generation in HepG2 cells [100]. These observations nicely fit into the concept that PIP3 is a strong stimulus for NADPH oxidase activation, as this phospholipid activates Akt and GEFs. Indeed, very recently, it has been shown that the PIP3-dependent activation of the RacGEF βPix increases Nox1-dependent radical generation in Caco-2 and HEK293 cells in response to the stimulation with the tyrosine kinase receptor agonist EGF [40]. In fact, there seems to exist a considerable amount of overlap in the action of the EGF receptor and the PDGF receptors on NADPH oxidase activation. Even the formation of active receptor heterodimers has been reported [101], and transactivation of the EGF receptor is a phenomenon observed for a wide variety of stimuli, including angiotensin II, thrombin, PDGF, lipids, and sphingosine 1-phosphate [102–104]. This certainly complicates the identification of the mechanism underlying NADPH oxidase activation in response to different stimuli, as EGF per se is a well-known activator of the oxidase [4,105]. It has even been suggested that radicals can trigger the activation of the NADPH oxidase by transactivation of tyrosine kinase receptors, such as the EGF receptor [106] and the PDGF β receptor [107]. More precisely, stimulation of VSMC with H2O2 via the activation of c-Src and PKC {delta} leads to autophosphorylation of the PDGF β receptor, and subsequently to activation of phospholipase C{gamma} [108].

Interestingly, some reports suggest that the signalling of the PDGF receptors is in part mediated via a tethering with G-protein-coupled receptors [109]. Using isolated membrane fractions, we observed that stimulation of VSMC with PDGF AA resulted in a rapid release of H2O2 in an ATP-independent manner, suggesting that an ATP-dependent tyrosine kinase activity was not involved in this process [96]. In contrast, this PDGF-induced radical formation was sensitive to pertussis toxin and to antibodies directed against p22phox and Gi1,2 [96]. Interestingly, activation of the insulin receptor in human adipocyte membrane preparations elicits a very similar signalling also involving G1,2 and not tyrosine kinase activity [110]. Recently, it was demonstrated that this effect of insulin in adipocytes is mediated via activation of a Nox4-containing NADPH oxidase [111]. Nox4 has been shown to be involved in constitutive radical generation in vascular cells, a demonstration of agonist-induced Nox4-dependent radical generation is still uncertain [42]. Nevertheless, it is tempting to speculate that the activation of the PDGF {alpha} receptor in VSMC results in a biphasic activation of different NADPH oxidase, involving a G-protein-coupled release of fatty acids [111] and subsequent activation of Nox4 in a first step with a secondary radical-mediated activation of other tyrosine kinases or tyrosine kinase receptors mediating Nox1-dependent radical generation (Fig. 4).


Figure 4
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  		Fig. 4 Hypothetical activation of the NADPH oxidase by ligands of platelet-derived growth factor (PDGF) receptors. Stimulation of PDGF β receptor leads to the activation of PI3-kinase. The activation of the PDGF {alpha} receptor in contrast activates inhibitory G-proteins and leads to a rapid release of H2O2 probably by Nox4. This process maybe involve the release of a fatty acids, i.e., phosphatidic acid (PA), induced by the action of Gi on phospholipases, probably phospholipase D (PLD). H2O2 subsequently activates Src, which leads to phosphorylation of tyrosine kinase receptors and subsequent activation of the oxidase via the PI3-kinase pathway.

 
Another important agonist for vascular radical generation involving tyrosine kinase receptors is vascular endothelial growth factor (VEGF; [112,113]), and VEGF-dependent ROS formation has been implicated to be essential for intricate endothelial functions as tube formation/angiogenesis and vascular permeability [113]. Activation of the VEGF-receptor KDR by its ligand within minutes leads to activation of Rac-1 [113], translocation of p47phox and increases in a Nox2-dependent radical formation in endothelial cells [113]. Interestingly, radical formation and the NADPH oxidase are essential for KDR autophosphorylation [113]. These data imply that autophosphorylation of KDR is not involved in radical generation, and that, as for the PDGF receptor, radical generation occurs in a receptor tyrosine kinase-independent fashion, as suggested recently [114].

5.2.3. Tumour necrosis factor alpha (TNF)
TNF plays a central role in several diseases associated with cellular activation and apoptosis. Using p22phox antisense strategies and dominant negative Rac-1, it was demonstrated that TNF activates the NADPH oxidase [6,115]. The signalling of TNF involves activation of PKC {zeta} in endothelial cells and is associated with PKC-mediated phosphorylation of p47phox and translocation of p47phox from the cytoplasm to the membrane where it interacts with gp91phox [116]. The TNF-induced radical production is strictly dependent on p47phox [117].

5.2.4. Hyperglycemia/glucose
Elevated glucose concentrations have been demonstrated to activate PKC isoforms and PI3-K (for review, see Ref. [118]). High glucose concentrations activate NADPH oxidases in a PKC-dependent manner [119], and inhibition of Rac-1 using 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) prevented this effect [120]. Most importantly, transfection of p47phox antisense oligonucleotides abrogated high-glucose-mediated signalling in mesangial cells [121]. The latter study is of particular importance as the interpretations of experiments using cultured endothelial cells or vascular segments are complicated by the fact that high glucose also leads to radical production via uncoupling of the endothelial nitric oxide synthase [122].

5.2.5. Lipids
5.2.5.1. Lysophosphatidic acid (LPA)
LPA is a bioactive lysophospholipid released from platelets, which via the action of different G-protein-coupled receptors (LPA1–3), activates G{alpha}i and G{alpha}12/13 [123]. In NIH 3T3 fibroblasts, LPA activates Rac in a pertussis toxin-sensitive manner [124]. In B103 cells overexpressing an LPA receptor, this effect was attributed to the GEF Tiam1 and the action of the LPA1 receptor [125]. Besides Rac, LPA mediates activation of PI3-K [125]. A similar action was observed in VMSC, where LPA rapidly stimulates the downstream target of Rac p21-PAK via pathways involving pertussis toxin-sensitive G-protein and c-Src [126]. In contrast, sphingosine-1-phosphate, which is also released from platelets and signals via similar receptors, does not activate NADPH oxidase [113] and even negatively regulates Rac activity in VSMC [127].

5.2.5.2. Oxidized LDL and lysophosphatidylcholine
It is long known that lysophosphatidylcholin (lysoPC), an elemental component of oxidized LDL, increases vascular radical generation in a PKC-dependent manner [128], and lysoPC has been shown to activate Rac [8]. The redox-mediated signalling of lysoPC was blocked by dominant-negative p47phox [129]. Accordingly, oxidized LDL increases vascular and endothelial cells radical generation [130] and transfection of p22phox antisense oligonucleotides blocked this effect [131]. The LPC-mediated activation of the endothelial NADPH oxidase is sensitive to inhibitors of phospholipase A2, PKC, and PI3-K [132].

5.2.6. Mechanical stimuli
5.2.6.1. Strain
Hypertension is a condition associated with increased vascular O2– generation, and increased levels of AngII are likely to contribute to oxidative stress. On the other hand, cyclic strain or stretch increases radical generation per se. A role for p47phox has been demonstrated in stretch-induced ROS formation in cultured mouse VSMC [133], and high pressure increases translocation [134] and phosphorylation of p47phox in isolated arteries via a calcium- and PKC-dependent pathway [135]. In contrast, application of a single stretch step decreases Rac activity in VSMC [136], whereas compression of VSMC increases Rac membrane association [137]. Vessels from animals subjected to prolonged hypertension exhibit increased NADPH oxidase-dependent radical formation and endothelial dysfunction, which is sensitive to inhibitors of PKC, the EGF receptor tyrosine kinase, and Rac [138]. Prolonged cyclic strain to VSMC induces HSP70, which is blocked by dominant-negative Rac [139]. In cultured endothelial cells, cyclic strain increased ROS formation, and this effect was also inhibited by transfection of dominant negative Rac [140]. Strain promotes angiotensin II-mediated effects on radical formation and activation of phospholipase D, and PKC seems to contribute to this process [141]. From this conglomerate of data, one may conclude that cyclic strain increases cellular radical formation via an NADPH oxidase, but further studies are needed to address the precise mode of activation of the enzyme and to understand the true function of Rac for strain-induced oxidase activation. Moreover, the role of the extracellular matrix and integrin binding, which might be critical for this process[142], has to be elucidated [142].

5.2.6.2. Shear stress
The continuous exposure of endothelial cells to the blood flow is thought to have a major role in the control of vascular homeostasis. Continuous laminar flow over endothelial cells increases NO production, NO synthase, and superoxide dismutase expression and is therefore considered to have antiatherosclerotic properties. Oscillatory flow in culture systems leads to the expression of a proatherosclerotic phenotype and is found in areas with high incidence of plaques. Sudden exposure of endothelial cells kept under static conditions to laminar flow leads to a transient activation of Rac, returning to baseline within one hour [143], which is a consequence of the new integrin binding to the extracellular matrix [144]. ROS formation paralleled Rac activity and was blocked by transfection of dominant negative Rac in endothelial cells [145]. Different to the transient increase in radical production upon acute onset of laminar flow, oscillatory flow leads to a sustained increase in radical production of endothelial cells [7], which is not observed in cells obtained from p47phox –/– mice [146].

5.2.7. Hypoxia–reoxygenation
Despite all the problems associated with the measurements of radicals under ischemia/reperfusion of vascular cell, this situation is associated with increased formation of radicals. Radical production was attenuated in p22phox antisense-treated endothelial cells [147] and in endothelial cells from gp91phox –/– mice [148]. Interestingly, increase in extracellular potassium, which leads to depolarization of the cell, mimicked perfusion-induced radical generation in a gp91phox-dependent manner [148]. Indeed, cellular depolarization results in the activation of Rac, which is associated with increases in tyrosine phosphorylation and radical formation, whereas hyperpolarization elicits the opposite effect [149].


   6. Conclusion
Top
 Abstract
 1. Introduction
 2. Structural components of...
 3. Assembly of NADPH...
 4. Upstream signalling and...
 5. Vascular NADPH oxidases
 6. Conclusion
References
 
The cellular radical generation has an important influence on the vascular homeostasis. Isoforms of the leukocyte-type NADPH oxidase expressed in different layer of the vessels under many conditions are sources of vascular radical formation. The vascular concentrations of the radicals generated by NADPH oxidases are controlled by different mechanisms, such as gene expression of the oxidase and of antioxidant enzymes, production of nitric oxide, and supply with antioxidative small molecules, energy, and oxygen. This review underscored that also acute regulation of enzyme activity via a very complex activation mechanism has a central role in the control of the vascular radical production. Several elements can be identified playing key roles in this process. Rac is activated by almost every cardiovascular factor studied [150], including AngII [86], PDGF [151], EGF [152], VEGF [153], TNF [154], thrombin [155], and lysophosphatidyl choline [8]. However, much additional work is needed to understand the mechanism underlying activation of Rac. It is important to realize that different GEFs vary in their capacity to elicit Rac-mediated NADPH oxidase activation [61], and almost nothing is know regarding the expression and activity of GEFs in the cardiovascular system. Other important signalling elements are PKC isoforms, the transactivation of tyrosine kinase receptors, and so far poorly defined NAPDH oxidase-activating lipids.


   Acknowledgements
 
This study was supported by a grant from the Deutsche Forschungsgemeinschaft to R.P.B. (BR1839/2-1).


   Notes
 
Time for primary review 19 days


   References
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 3. Assembly of NADPH...
 4. Upstream signalling and...
 5. Vascular NADPH oxidases
 6. Conclusion
 References
 

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