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Cardiovascular Research 2007 75(4):679-689; doi:10.1016/j.cardiores.2007.06.016
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Copyright © 2007, European Society of Cardiology

Adventitial fibroblast reactive oxygen species as autacrine and paracrine mediators of remodeling: Bellwether for vascular disease?

Mounir J. Haurania and Patrick J. Pagano*,b

aHenry Ford Hospital, Detroit MI, Department of General Surgery, United States
bHenry Ford Hospital, Detroit MI, Hypertension and Vascular Research Division, United States

* Corresponding author. Hypertension and Vascular Research Division, RM 7044, E&R Bldg., Henry Ford Hospital, 2799 West Grand Blvd., Detroit, MI 48202-2689, United States. Tel.: +1 313 916 7055; fax: +1 313 916 1479. PPAGANO1{at}hfhs.org

Received 30 January 2007; revised 18 June 2007; accepted 19 June 2007


   Abstract
Top
 Abstract
1. Introduction
 2. Functional role of...
 3. Functional role of...
 4. Role of adventitial...
 5. NAD(P)H oxidase as...
 6. Comparison with vascular...
 7. Activators of adventitial...
 8. Role of ROS...
 9. Role of ROS...
 10. Role of ROS...
 11. Role of ROS...
 12. Summary
 References
 
The importance of the vascular adventitia is increasingly being recognized not only in vascular disease but also in normal maintenance and homeostasis of vessels. Activation of the adventitia and its resident fibrocytic cells in response to injury, stretch, cytokines, and hormones has been shown to stimulate differentiation, collagen deposition, migration, and proliferation. Importantly, the effects of adventitial fibroblasts are increasingly being ascribed to reactive oxygen species (ROS) produced by adventitial fibroblast NAD(P)H oxidases. Much historical and recent evidence suggests that fibroblast NAD(P)H oxidase) is a harbinger and initiator of vascular disease and remodeling. Data from our laboratory indicate that adventitial fibroblast NAD(P)H oxidase plays a direct and/or paracrine role in neointimal hyperplasia as well as a paracrine role in medial smooth muscle hypertrophy in vivo. We propose that adventitial NAD(P)H oxidase-derived cell-permeant hydrogen peroxide or a byproduct of its oxidation of lipids activates signaling mechanisms in medial smooth muscle leading to the growth response. This review will address the potential role of this adventitial ROS in vascular inflammation and cytokine release to potentiate smooth muscle hypertrophy. We will also survey other signaling pathways involving adventitial NAD(P)H oxidase ultimately leading to changes in vascular phenotype.

KEYWORDS NADPH Oxidase; Adventitia; Paracrine; Hypertrophy; Fibroblast; Autocrine; Remodeling; Reactive oxygen species; Free radicals


   1. Introduction
Top
 Abstract
 1. Introduction
2. Functional role of...
 3. Functional role of...
 4. Role of adventitial...
 5. NAD(P)H oxidase as...
 6. Comparison with vascular...
 7. Activators of adventitial...
 8. Role of ROS...
 9. Role of ROS...
 10. Role of ROS...
 11. Role of ROS...
 12. Summary
 References
 
Hypertensive vascular disease is a major risk factor for a variety of cardiovascular diseases including stroke, myocardial infarction, congestive heart failure and renal microvascular disease. Undoubtedly, the mechanisms involved are complex, however there is now compelling evidence that an increase in reactive oxygen species (ROS) during hypertension plays a pivotal role in this process. Studies suggest that in hypertension and other vascular disease, there is an imbalance in oxidant-generating vs. oxidant-catalyzing systems, leading to a build-up of endogenous superoxide anion (O2–) and hydrogen peroxide (H2O2). The vascular adventitia is a major site of vascular ROS production and it appears that adventitial fibroblast NAD(P)H oxidase-derived ROS is the sensor and messenger for the early development of vascular disease. This review will focus on the contribution of adventitial fibroblasts, their NAD(P)H oxidase(s) and the role of attendant ROS in neointimal growth and medial hypertrophy in systemic arteries.

Curiously, until recently the contribution of the adventitia to vascular function has largely been ignored except for an occasional mention that it provides support for the blood vessel (extracellular matrix) and a scaffold for sympathetic nerve endings and the vasa vasorum. Much attention has been given to the paracrine role of the vascular endothelium-derived hormones in the past 20 years since the discovery of endothelium-derived relaxing factor. Before that the endothelium was treated with the same indifference as the adventitia, largely considered an inert physical barrier separating the medial smooth muscle from other tissues. This "outsider" status of the adventitia is clearly giving way to a rapidly growing interest in this relatively new frontier in vascular biology.


   2. Functional role of adventitial fibroblasts in vasculogenesis and angiogenesis
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 Abstract
 1. Introduction
 2. Functional role of...
3. Functional role of...
 4. Role of adventitial...
 5. NAD(P)H oxidase as...
 6. Comparison with vascular...
 7. Activators of adventitial...
 8. Role of ROS...
 9. Role of ROS...
 10. Role of ROS...
 11. Role of ROS...
 12. Summary
 References
 
The development of the vasculature is a complex process that is still not completely understood. There appears to be both predetermined genetic influences as well as stimuli from the local environment. Genetic coding predetermines the axial pattern of vessel development, and single gene mutations have been shown to lead to abnormal vessel formation [1]. In addition to predetermined genetic influences on vasculogenesis, it appears that angiogenesis is influenced by local conditions such as hypoxia and nutrient demand [2–6]. Angiogenesis and the formation of primitive endothelial tubes have been shown to be promoted by fibroblasts and NAD(P)H oxidases [7–9]. Inasmuch as the vascular NAD(P)H oxidase isoforms discovered to date have been shown to modulate cell propagation and differentiation of mature cells [10–12], close examination of the unique combination of oxidase isoforms and their function in the nascent adventitial fibroblast (see Table 1 and Fig. 1) is expected to shed light on the fundamental role of the fibroblast oxidase in vascular development.


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  		Table 1 Expression of NADPH oxidase components in vascular parenchymal cells

 

Figure 1
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  		Fig. 1 Schematic showing VSMC and adventitial fibroblast oxidase isoforms reported to date in large and small blood vessels. Structural compositions of the various membrane-spanning NADPH oxidase subunits (cytochrome) are depicted along with the differentially required cytosolic subunits necessary for activation. VSMC contain nox1, nox2, and nox4, while adventitial fibroblasts do not appear to contain nox1. The predominant isoforms in adventitial fibroblasts appears to be nox4 which does not appear to require cytosolic subunits for activity like nox2 and nox1. These differences between VSMC and fibroblasts with regard to the array of NADPH oxidases present as well as their magnitude and activities are expected to play an important distinguishing role in individual cell phenotypes.

 

   3. Functional role of adventitial fibroblasts in medial hypertrophy and neointimal growth
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 Abstract
 1. Introduction
 2. Functional role of...
 3. Functional role of...
4. Role of adventitial...
 5. NAD(P)H oxidase as...
 6. Comparison with vascular...
 7. Activators of adventitial...
 8. Role of ROS...
 9. Role of ROS...
 10. Role of ROS...
 11. Role of ROS...
 12. Summary
 References
 
A provocative study by Wang et al. suggested a paracrine effect of ROS on medial hypertrophy [13]. AngII was shown to stimulate NAD(P)H oxidase-derived ROS in mouse aortic adventitia and intima, concomitant with medial hypertrophy. Moreover, this stimulation was significantly reduced in nox2-deficient mice exhibiting reduced intimal and adventitial NAD(P)H oxidase, suggesting a paracrine effect of adventitial and intimal NAD(P)H oxidase-derived ROS on medial hypertrophy [13]. Findings by our laboratory suggest a more complex in vivo scenario of a potentiated medial hypertrophy as a consequence of ROS derived from the adventitia. We postulated that adventitial NAD(P)H oxidase-derived H2O2 per se could influence medial hypertrophy. To test this hypothesis, we used an adenoviral construct designed with the intent to target expression of an inhibitor of nox2:p47phox interaction (gp91ds, now referred to as nox2ds) to the mouse carotid artery adventitial fibroblasts. However, to our surprise we identified expression of the inhibitor in a subset of macrophages in addition to adventitial fibroblasts (Fig. 2A). This inhibitor expression had the proposed effect as it significantly reduced medial ROS and hypertrophy (Fig. 2B–F) [14]. It is important to point out that in AngII-induced hypertension others have shown that macrophages localize in the adventitia and have been implicated in medial smooth muscle hypertrophy [15]; yet the contribution of ROS or cytokines derived from these cells has not been delineated to our knowledge [16]. ROS derived from adventitial fibroblasts may be chemotactic for macrophages [17], which through their larger oxidase potential exacerbate ROS levels in the adventitia and enhance pro-hypertrophic mechanisms. Intriguingly, these unexpected findings provided us with a new perspective on the role of inflammation and inflammatory cells in this process (see further discussion below on the interaction of oxidative stress and inflammation). However, regardless of the particular cell type involved in these studies, the data supported a paracrine effect of adventitial NAD(P)H oxidase-derived ROS on medial hypertrophy.


Figure 2
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  		Fig. 2 The adventitia plays a critical role in the modulation of AngII-induced vascular hypertrophy. Panel A. shows transfection of the adventitia with an adenovirus co-expressing an inhibitor of nox2 as well as eGFP. Brown staining indicates transfection with the virus (antibody against eGFP). Notice the transfection confined to the adventitia. The black arrow indicates fusiform fibroblasts in the adventitia, the red arrow indicates macrophages, and the purple arrow un-transfected macrophages (confirmed via specific staining for macrophages, not shown here). Panels B–D show Masson Trichrome treated cross-sections of mouse carotid artery staining medial smooth muscle cells in pink and adventitial collagen in blue. Carotid sections in B. are from vehicle treated mice, in C. from AngII-infused mice transfected with control virus, and D. AngII-infused mice transfected with the virus expressing the nox2ds inhibitor. As seen in the figure, AngII induces carotid medial thickening, which is reversed by inhibitor virus. Panels E–G demonstrate sections of carotids from the same animal treatment groups in the same order (as B–D) illustrating ROS as detected by 4-HNE immunohistochemistry. The increase in ROS (brown staining) in AngII-infused vs. control mice is reversed by the transfection of the inhibitor virus.

 
An abundance of data indicate a role for adventitial fibroblasts in neointimal hyperplasia. One of the most prominent of these was carried out by Scott et al. in domestic juvenile swine that underwent standard clinical angioplasty of the left anterior descending and circumflex coronary arteries [18]. At the earliest time points after angioplasty the largest number of proliferating cells could be found in the adventitia. Cell proliferation was greatest at the site of the medial tear but was also found at the circumference of the entire vessel. Interestingly, at 7 days cell proliferation abated in the adventitia and rose in the neointima [18]. Indeed Wilcox and coworkers referred to the adventitia as a "first wave of growth" after coronary artery angioplasty [19]. Scott's findings were elegantly corroborated by studies performed by Li et al. who tracked syngeneic fibroblasts derived from the rat carotid adventitia and transformed with β-galactosidase. By detecting vectorial migration of adventitial myofibroblasts into the neointima over time after balloon injury, they convincingly demonstrated the ability of adventitial cells to contribute to neointimal growth [20]. However there are contradictory findings by De Leon et al. showing that adventitial cells labeled with a fluorescent dye did not migrate after balloon angioplasty of the rat carotid artery [21], which these authors explained could be attributed to a milder balloon injury that did not compromise the elastic laminae. Taken together with the knowledge that NAD(P)H oxidase activation in fibroblast precedes proliferation and neointimal growth, these findings appeared to confer a prominent status to the adventitial fibroblast NAD(P)H oxidase as an initiator of vascular remodeling in moderate to severe injury. When combined with the established ability of fibroblasts and myofibroblasts to produce a variety of inflammatory cytokines, growth factors, and extracellular matrix, the current literature is consistent with an instrumental role for adventitial fibroblast in vascular remodeling.


   4. Role of adventitial fibroblasts as the first responder and initiator of vascular remodeling
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 Abstract
 1. Introduction
 2. Functional role of...
 3. Functional role of...
 4. Role of adventitial...
5. NAD(P)H oxidase as...
 6. Comparison with vascular...
 7. Activators of adventitial...
 8. Role of ROS...
 9. Role of ROS...
 10. Role of ROS...
 11. Role of ROS...
 12. Summary
 References
 
Hypertension, atherosclerosis, and vascular injury all activate adventitial cells and increase macrophage levels in the perivascular space [17,18,22–24]. In 1915, Allbutt [25] reported the presence of inflammatory cells in the perivascular adventitia of atherosclerotic arteries. In 1962, Schwartz and Mitchell [26] showed a positive correlation between the magnitude of adventitial inflammation and the severity of atherosclerosis. The local combination of adventitial fibroblasts with the activated leukocyte respiratory burst oxidase may be expected to potentiate production of adventitial ROS. AngII generation and cytokine release by perivascular cells can be expected to synergize in an excessive ROS production. In fact, many groups including our own have illustrated that the adventitia and its fibroblasts have a great capacity to produce ROS under both quiescent and pathological conditions [23,24,27–29]. The localized production of AngII in the perivascular space along with a pronounced sensitivity to AngII in the production of ROS [29] suggested that these cells could play an important role in vascular diseases.

In addition, the importance of the adventitia is further highlighted by its proposed role as a "first-responder" during early disease development [18,25,26,30–33]. For example, Arribas et al. showed that in a model of chronic nitric oxide inhibition which greatly enhanced systolic blood pressure, adventitial cell number and adventitial thickness were markedly increased. This adventitial response is in sharp contrast to medial and intimal thickness that exhibited no change in thickness after 3 weeks of hypertension [30]. In addition, in mesenteric arteries from animals conditionally transgenic for the renin-2 gene (Ren-2) in which blood pressure was greatly enhanced, significant increases in adventitial cell number and density were observed at 14 days whereas smooth muscle and endothelial cells remained unchanged [34]. Since medial hypertrophy and thickening are eventual hallmarks of sustained elevation of blood pressure, these findings appeared to suggest that adventitial remodeling in the early stages of hypertension is a signal for later widespread vascular wall growth.

A few landmark studies of the pulmonary artery indicate striking increases in adventitial cell proliferation and thickness. First, autopsied pulmonary arteries from patients with primary pulmonary hypertension (PPH) demonstrated markedly higher adventitial thickness, which the authors attributed to higher fibroblast proliferation and collagen deposition [35]. Belknap and coworkers examined BrdU incorporation in neonatal calf pulmonary arteries and observed a temporal increase in medial and adventitial cell proliferation in hypoxic calves compared to control; more importantly, they demonstrated remarkably higher adventitial vs. medial cell proliferation 1 day after commencement of hypoxia, which preceded the initial increase in medial cell proliferation at 4 days [36]. Even more striking was the finding that BrdU labeling during the postpartum pulmonary transition was still far greater than 3H-thymidine incorporation reported in the adult pulmonary artery indicating a major role for hypoxia in this response. Additionally, in response to both renovascular hypertension and hypercholesterolemia in the pig, adventitial remodeling of the coronary artery occurs early in the disease, often preceding endothelial dysfunction [37,38].


   5. NAD(P)H oxidase as a source of ROS in adventitial fibroblasts
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 Abstract
 1. Introduction
 2. Functional role of...
 3. Functional role of...
 4. Role of adventitial...
 5. NAD(P)H oxidase as...
6. Comparison with vascular...
 7. Activators of adventitial...
 8. Role of ROS...
 9. Role of ROS...
 10. Role of ROS...
 11. Role of ROS...
 12. Summary
 References
 
Reactive oxygen species (ROS) represent a broad class of molecules derived from the metabolism of oxygen and include free radical and non radical species which are generally capable of oxidizing molecular targets. O2– is considered the forerunner of all ROS because it is, in most cases, the first ROS produced by mammalian oxidases. This is clearly true in the vasculature in which the primary source of ROS has been identified as NAD(P)H oxidase [28,39–41]. In addition to the in depth characterization of this important ROS source in endothelial cells and smooth muscle, we initially identified a major vascular source of ROS in rabbit vascular adventitial fibroblasts as NAD(P)H oxidase [28]. These studies led to others showing that under basal conditions a major source of vascular O2– generating activity in rats and mice is adventitial fibroblast NAD(P)H oxidase [13,27,42–45].

Adventitial fibroblast NAD(P)H oxidase activity is highly sensitive to induction by the pro-constrictor and pro-inflammatory AngII [29] and contains at least four major neutrophil-like NAD(P)H oxidase components, p22phox, p47phox, p67phox and nox2 (previously termed gp91phox) [29]. We showed that immuno-sedimentation of p67phox from fibroblast membrane fractions caused a major decrease in oxidase activity. Upon cloning p67phox from rabbit adventitial fibroblasts 95% nucleotide sequence homology and a predicted 89% amino acid homology was found in comparison with human phagocyte p67phox [46]. Taken together with the high degree of homology of the fibroblast nox2 and phagocyte nox2 [47], it was clear that the ROS-generating system in adventitial fibroblasts is remarkably well conserved and similar to the phagocyte system. To our knowledge, the degree of homology we reported surpasses that of any other vascular oxidase component cloned to date. On the other hand, important differences were noted in the fibroblast vs. phagocyte oxidase, e.g., a relatively small capacity to produce ROS as well as a constitutive activity [29,46]. These hallmark differences suggested at the outset of our studies that adventitial fibroblast NAD(P)H oxidase would subserve markedly distinct functions in the vascular wall in comparison with the antimicrobial action of phagocytes. Since these early studies, reports by Sorescu et al. have uncovered the presence of the high capacity nox2 homologue nox4 in the adventitia although its role there is still unclear [48]. Relevant to this point, other groups have confirmed that the adventitia or adventitial fibroblasts possess high specific activity of NAD(P)H oxidase relative to other vascular segments [23,24,27].


   6. Comparison with vascular smooth muscle and endothelial NAD(P)H oxidase
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 Abstract
 1. Introduction
 2. Functional role of...
 3. Functional role of...
 4. Role of adventitial...
 5. NAD(P)H oxidase as...
 6. Comparison with vascular...
7. Activators of adventitial...
 8. Role of ROS...
 9. Role of ROS...
 10. Role of ROS...
 11. Role of ROS...
 12. Summary
 References
 
Multiple studies have found considerable differences between the adventitial fibroblast NAD(P)H oxidase and those of VSMC and endothelial cells [28,29,39,49]. In early reports, VSMC were shown to express critical phagocyte-like NAD(P)H oxidase components [50–52] as well as an important homologue of the essential phagocyte anchoring component (nox2), nox1, that clearly participates in vascular O2– production and cell proliferation [12,52,53]. In most of these studies, AngII is the prototype stimulus for smooth muscle NAD(P)H oxidases [39], save for nox4 which appears to be down-regulated by AngII. Whereas conduit vessel smooth muscle possess a functional nox1 and nox4 but little or no nox2, nox2 appears to predominate in resistance artery smooth muscle cells [52]. Interestingly, while nox4 reportedly has the greatest capacity to produce ROS, it has been implicated in promoting cell senescence [54,55]. Likewise, endothelial cells contain nox2 and at least one of its homologues, nox4, which are functionally involved in O2– production and endothelial dysfunction [49,56–58]. While most studies confirm that NAD(P)H oxidases produce O2–, some contend that these enzymes, particularly nox4, can directly produce H2O2 [59] although this may also be explained by its intracellular location and the subsequent rapid dismutation of O2– into H2O2 [60] (see Table 1 and Fig. 1).


   7. Activators of adventitial fibroblast NAD(P)H oxidase
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 Abstract
 1. Introduction
 2. Functional role of...
 3. Functional role of...
 4. Role of adventitial...
 5. NAD(P)H oxidase as...
 6. Comparison with vascular...
 7. Activators of adventitial...
8. Role of ROS...
 9. Role of ROS...
 10. Role of ROS...
 11. Role of ROS...
 12. Summary
 References
 
The adventitial NAD(P)H oxidase is known to be induced by a wide variety of activators ranging from changes in mechanical force to metabolic diseases including atherosclerosis and diabetes (Fig. 3). Over the past decade, cyclic strain has been shown to cause oxidative stress in a variety of vascular cells [61–64] and a couple of studies demonstrate that simple stretch of arteries activates NAD(P)H oxidase [65,66]. In fact, Souza et al. [67] demonstrated rapid and massive increases in NAD(P)H oxidase-derived O2– by a balloon catheter. Our data showed that a specific NAD(P)H oxidase inhibitor (nox2ds-tat, previously referred to as gp91ds-tat) significantly attenuated this increase and neointimal growth in the rat carotid artery [67]. The ramifications of this oxidase activation have been established to include restenosis; consistent with NAD(P)H oxidase-derived H2O2 activating growth-signaling pathways, leading to proliferation and migration of adventitial fibroblasts and VSMCs [23,68–71]. Moreover, a multitude of studies clearly demonstrate a link between metabolic factors in atherosclerosis and diabetes mellitus and the oxidase [24,72–74]. Of particular note, essential component p47phox is reportedly required for progression of atherosclerosis in apoE-deficient mice fed a high fat diet [75].


Figure 3
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  		Fig. 3 Schematic representation of the known and proposed activators of adventitial NAD(P)H oxidase and its proposed paracrine effects on VSMCs.

 
In the pulmonary adventitia, much of the focus has been on the role of hypoxia in the induction of fibroblast proliferation. Pulmonary adventitial fibroblasts are highly sensitive to hypoxia and AngII, which cause fibroblast proliferation leading up to pulmonary hypertension [76,77]. In these and other studies, hypoxia is implicated in the activation of fibroblast NAD(P)H oxidase, including the specific role of nox2 [78]. Kuwahara et al. provide provocative data correlating hypoxia in the outer media and adventitia with VEGF and HIF-1{alpha} expression [79]; in fact VEGF has been shown to be induced and secreted in the adventitia [79].

Finally, a considerable body of data establishes a role for inflammatory cytokines and growth factors in the activation of fibroblast oxidase. A recent report by Lee and coworkers advances the concept of an important role of cytokines in AngII-induced hypertension. The authors showed that IL-6-knockout mice exhibited a less-sustained mean arterial pressure in response to AngII infusion over 14 days [80]. These data may suggest an important role for cytokines in the activation of vascular NAD(P)H oxidases, leading to further cytokine release and a feed-forward cycle promoting remodeling [81,82]. In addition to the plethora of effects of AngII as a vascular pro-growth factor involving NAD(P)H oxidase, since the inception of this field of study of vascular oxidases it has been known that transforming growth factor-beta1 (TGFβ-1) is a potent activator of fibroblast NAD(P)H oxidase [83]. Even earlier, Meier et al. showed that IL-1 and TNF-{alpha} stimulated the release of ROS from human fibroblasts [84]. Although there is considerable evidence that vascular fibroblasts and smooth muscle cells produce and release an array of cytokines and growth factors [85–89], to date there is little evidence that this release is mediated by NAD(P)H oxidases [90]. Thus a substantial amount of work is required to examine our proposal that VSMC and adventitial fibroblasts display autocrine and paracrine effects on vascular hypertrophy via a cycle of cytokine release and the activation of NAD(P)H oxidases (Fig. 3).


   8. Role of ROS derived from adventitial NAD(P)H oxidase in vascular biology: H2O2 and its potential importance as a paracrine factor
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 Abstract
 1. Introduction
 2. Functional role of...
 3. Functional role of...
 4. Role of adventitial...
 5. NAD(P)H oxidase as...
 6. Comparison with vascular...
 7. Activators of adventitial...
 8. Role of ROS...
9. Role of ROS...
 10. Role of ROS...
 11. Role of ROS...
 12. Summary
 References
 
In recent years, emerging evidence from our laboratory and others has supported a central role for adventitial fibroblast-derived ROS in vascular cell proliferation and medial hypertrophy [14,17,23,70,71,91–93]. Importantly, we showed that specific inhibition of adventitial NADPH oxidase-derived ROS in AngII-induced hypertension causes attenuation of ROS across the vessel wall and proposed tissue-permeant H2O2 (or one of its metabolites) as the most likely paracrine agent(s) derived from the adventitia signaling to the media [14]. Similarly, other groups have proposed that H2O2 promotes a feed-forward propagation of ROS production in the vasculature [94,95]. The rapid growth of this field and the realization that ROS can act as tissue signaling agents [96] have lent new significance to the role of the adventitia in vascular function. O2– has been described as an intracellular signaling agent capable of activating key kinases and phosphatases involved in contraction and cell growth [97]. In addition, in the central nervous system O2– derived from NAD(P)H oxidase appears to be the critical signaling moiety involved in the AngII-induced drinking response [98]. Thus O2– is capable of cellular signal transduction and is likely to play a role in intracellular or highly localized signaling. However, O2– is not a likely paracrine mediator of AngII-induced medial hypertrophy or impaired vascular tone since its half-life and radius of diffusion are extremely short [99,100]. H2O2 is likely a better candidate for paracrine effects across the vessel wall. For one, H2O2 is a cell-permeant and highly stable ROS generated primarily by dismutation of O2– by superoxide dismutases (SOD). Although H2O2 is defined as a ROS, unlike O2– it is not a free radical, in that it does not possess an unpaired electron in its outer shell. This renders H2O2 more stable and less reactive with other tissue radicals, and thus a more likely paracrine ROS. Relevant to highly localized autocrine effects, in the presence of iron intracellular H2O2 may be converted to the unstable hydroxyl radical, a strong oxidant that can oxidize molecular targets and cause lipid peroxidation [101,102].


   9. Role of ROS derived from adventitial NAD(P)H oxidase in vascular biology: mediator of vascular dysfunction?
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 Abstract
 1. Introduction
 2. Functional role of...
 3. Functional role of...
 4. Role of adventitial...
 5. NAD(P)H oxidase as...
 6. Comparison with vascular...
 7. Activators of adventitial...
 8. Role of ROS...
 9. Role of ROS...
10. Role of ROS...
 11. Role of ROS...
 12. Summary
 References
 
Having established the adventitia as a major source of tissue-permeant ROS and suggested it to be H2O2 [14], it is important to address the mechanisms whereby elevated concentrations of H2O2 lead to vascular growth and dysfunction. The manifold effects of H2O2 on vascular tone are important but are outside the scope of this discussion, and thus we refer the reader to our recent review on the topic [103]. Intriguingly, one report by Shi-Wen et al. suggests that increased activity of adventitial myofibroblasts contributes to significant changes in the structure and function of conduit and muscular arteries. They explain that increased extracellular matrix production as well as the ability of myofibroblasts to contract may be involved in these changes [104]. Since H2O2 and other ROS are known to promote phenotypic differentiation of fibroblasts to myofibroblasts [23,69], heightened constriction may be expected in vessels with increased adventitial ROS production by virtue of an increased density of adventitial myofibroblasts. With a view toward the broad effects of NO on vessel growth, it is important to note that H2O2 can reduce vascular NO production. One intriguing paper by Wedgwood and Black suggests that endothelin 1-induced stimulation of H2O2 release in pulmonary VSMCs decreases eNOS expression and activity in pulmonary endothelial cells [105]. Another interesting study demonstrated a H2O2-induced decrease in gene expression of inducible NOS (iNOS) [106]. Finally, Jaimes et al. showed that H2O2 decreased NO production by inactivation of eNOS cofactors without affecting eNOS activity [107].

At this juncture, it is important to discuss recent reports revealing that H2O2 stimulates eNOS and SOD, resulting in higher NO levels [108,109]. Cai et al. intriguingly demonstrate that concomitant induction of NOS and SOD by H2O2 could explain the preservation of NO despite increased O2– [108] and point to a compensatory mechanism of NO protection under some conditions and in some vascular beds. However, most reports, including our own, have suggested that O2– levels outpace elevations in NO [110–112]. One mechanism by which H2O2 promotes such an increase is through dysfunction of NOS, just as it may stimulate phagocyte-like oxidases to produce more O2–, H2O2 and other ROS [95,113]. Taken together, these data appear to suggest that H2O2 plays an important role in the regulation of NOS activity and in the biological fate of NO, leading to overall reduced NO bioactivity.


   10. Role of ROS derived from adventitial NAD(P)H oxidase in vascular biology: mediator of VSMC signaling
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 Abstract
 1. Introduction
 2. Functional role of...
 3. Functional role of...
 4. Role of adventitial...
 5. NAD(P)H oxidase as...
 6. Comparison with vascular...
 7. Activators of adventitial...
 8. Role of ROS...
 9. Role of ROS...
 10. Role of ROS...
11. Role of ROS...
 12. Summary
 References
 
Early reports by Griendling and coworkers established that H2O2 metabolized from NAD(P)H oxidase-derived O2– mediated AngII-induced hypertrophy of cultured smooth muscle cells [114]. Ushio-Fukai et al. elegantly showed that NAD(P)H oxidase cytochrome component p22-phox was critical to this hypertrophic process [50]. Since then numerous studies have demonstrated a role for ROS in the activation of both proximal and downstream mitogen-activated protein kinases (MAPKs) [96]. H2O2 derived from NAD(P)H oxidase has been implicated in the activation of c-Src, which in turn transactivates receptor tyrosine kinases [40,66]. Activation of phosphatidyl inositol (PI)3-kinase is downstream of epidermal growth factor receptor (EGF-R) and required for NAD(P)H oxidase activation [40]. The resulting tyrosine phosphorylation generally leads to activation of src homology complex-growth factor receptor-bound protein 2 ’ son of sevenless complex (Shc-Grb2-Sos) that activates ras, leading to downstream activation of Rho-kinase, MAPKs and transcription factors. Some of the key redox-sensitive kinases in these signaling pathways are extracellular-regulated kinase (ERK), c-Jun N-terminal kinases (JNK), big MAPK (ERK 5), and p38 MAPK [115–117]. Furthermore, Ushio-Fukai and coworkers were the first to show the role for redox-sensitive Akt in vascular hypertrophy [118]. Importantly, a recent study by Zhang et al. elegantly demonstrated that human catalase overexpression in VSMC decreases the hypertrophic effect of AngII-induced hypertension, emphasizing the important local role of H2O2 in vivo [119]. Thus, drawing collectively from these studies, it is evident that H2O2 is an important cellular signaling molecule in pathways leading to VSMC hypertrophy.


   11. Role of ROS derived from adventitial NAD(P)H oxidase in vascular biology: mediator of inflammation
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 Abstract
 1. Introduction
 2. Functional role of...
 3. Functional role of...
 4. Role of adventitial...
 5. NAD(P)H oxidase as...
 6. Comparison with vascular...
 7. Activators of adventitial...
 8. Role of ROS...
 9. Role of ROS...
 10. Role of ROS...
 11. Role of ROS...
12. Summary
 References
 
Oxidative stress may be defined as a cellular/tissue imbalance of ROS resulting in reduced cellular defenses. A variety of studies illustrate an association between oxidative stress and the pro-inflammatory mediators MCP-1 and IL-6 in the perivascular region in cardiovascular disease [72,120–122]. Studies also show that NAD(P)H oxidase activity [14,17,39,40,114] and MCP-1 and IL-6 release are increased in response to AngII [86,123]. Since oxidative stress mediates vascular release of MCP-1 and IL-6, a link between adventitial H2O2 production and inflammation may easily be inferred [82,124]. Interestingly, both MCP-1 and IL-6 contribute to cardiomyocyte hypertrophy [125,126], and the preponderance of evidence supports a pro-growth effect of MCP-1on VSMCs [127,128], except for one report that MCP-1 inhibits growth [129]. Taken together, these findings suggest that oxidative stress in the adventitia could potentially lead to pro-growth cytokines/factors that stimulate medial hypertrophy.

The signaling mechanisms acted upon by these mediators are consistent with cell growth. For example, ERK1/2, NF-{kappa}B and AP-1 are downstream effectors of MCP-1 [130]. Moreover, AngII and MCP-1 activate ERK1/2 [130–132], NF-{kappa}B and AP-1 which are known to be sequentially linked to cell growth [86,133–136].


   12. Summary
Top
 Abstract
 1. Introduction
 2. Functional role of...
 3. Functional role of...
 4. Role of adventitial...
 5. NAD(P)H oxidase as...
 6. Comparison with vascular...
 7. Activators of adventitial...
 8. Role of ROS...
 9. Role of ROS...
 10. Role of ROS...
 11. Role of ROS...
 12. Summary
References
 
Adventitial hyperplasia and activation has been described as a precursor for remodeling and/or end-organ damage in a variety of vascular disease models. Evidence from a variety of laboratories indicates that adventitial fibroblast NAD(P)H oxidase is a major source of O2– in the vascular wall and that upon dismutation of O2– to H2O2, the latter promotes fibroblast hyperplasia and permeates the vascular media promoting vascular hypertrophy. Under normal conditions, constitutive oxidase activities and endogenous scavenger systems, including catalase and glutathione peroxidases, maintain a homeostatic balance in favor of normal wall thickness. However, we postulate that upon stimulation of the various oxidases by mechanical stretch and/or vasoactive hormones, increased production of peroxide and/or the release of cytokines participate in a feed-forward activation of vascular nox isoforms leading to abnormally high levels of growth-promoting peroxide. During this process, the adventitial NAD(P)H oxidase is expected to produce large amounts of H2O2, that eventually tips the balance in favor of an inflammatory response synergizing in the induction of medial hypertrophy and potentially vascular damage. With growing evidence of a feed-forward relationship among the oxidases, careful examination of the individual nox isoforms and their production of H2O2 is expected to be an area of intense study.

Time for primary review 19 days


   References
Top
 Abstract
 1. Introduction
 2. Functional role of...
 3. Functional role of...
 4. Role of adventitial...
 5. NAD(P)H oxidase as...
 6. Comparison with vascular...
 7. Activators of adventitial...
 8. Role of ROS...
 9. Role of ROS...
 10. Role of ROS...
 11. Role of ROS...
 12. Summary
 References
 

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