Skip Navigation

Cardiovascular Research 2007 75(4):659-668; doi:10.1016/j.cardiores.2007.06.007
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Siow, R. C.M.
Right arrow Articles by Churchman, A. T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Siow, R. C.M.
Right arrow Articles by Churchman, A. T.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 2007, European Society of Cardiology

Adventitial growth factor signalling and vascular remodelling: Potential of perivascular gene transfer from the outside-in

Richard C.M. Siow* and Adrian T. Churchman

Cardiovascular Division, School of Medicine, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom

* Corresponding author. Cardiovascular Division, School of Medicine, King's College London, 3.21 Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, United Kingdom. Tel.: +44 20 7848 4333; fax: +44 20 7848 4500. richard.siow{at}kcl.ac.uk

Received 22 March 2007; revised 22 May 2007; accepted 7 June 2007


   Abstract
Top
 Abstract
1. Introduction
 2. Growth factors in...
 3. Perivascular gene transfer...
 4. Role of adventitial...
 5. Adventitial extracellular...
 6. Adventitial oxidative stress...
 7. Antioxidant genes and...
 8. Summary and future...
 References
 
The adventitial segment of the vessel wall has received limited attention compared the endothelium, media and neointima in processes involved in vascular remodelling during atherogenesis, coronary artery bypass graft failure and in response to angioplasty. The adventitia has been regarded as a relatively ‘inert’ layer providing a supportive connective tissue and extracellular matrix scaffold around vessels for nerves and the vasa vasorum. We and others have recently demonstrated that functional changes in cells within the adventitia contribute to vascular remodelling through the activation and migration of adventitial myofibroblasts, partly under the influence of transforming growth factor-β1 and platelet derived growth factor-BB. These cytokines stimulate local accumulation of progenitor cells, angiogenesis, matrix deposition and enhanced generation of reactive oxygen species, together contributing to intimal hyperplasia in vascular diseases. This review summarises the evidence that growth factors acting locally in the adventitia can influence vascular function. Furthermore we highlight the therapeutic potential of perivascular gene transfer approaches from the ‘outside-in’ to antagonise growth factor activity and to modulate expression of vaso- and redox-active genes which act in concert to prevent the progression of vascular diseases in which adventitial cells are activated.

KEYWORDS Adventitia; Atherosclerosis; Restenosis; Coronary artery bypass graft; Growth factor; Vascular remodelling; Progenitor cells; Smooth muscle cells; Myofibroblasts; Reactive oxygen species; Antioxidant genes; Gene therapy


   1. Introduction
Top
 Abstract
 1. Introduction
2. Growth factors in...
 3. Perivascular gene transfer...
 4. Role of adventitial...
 5. Adventitial extracellular...
 6. Adventitial oxidative stress...
 7. Antioxidant genes and...
 8. Summary and future...
 References
 
The capacity of the adventitia to influence neointima formation and vascular remodelling has received increasing attention over the past decade [1,2]. Histological delineation of the compartments of the arterial wall is largely historical, with the adventitia being regarded as a relatively inert layer providing a scaffold comprising of extracellular matrix and connective tissue for sympathetic nerve endings and the vasa vasorum, while the medial and intimal layers were considered to be more active participants in atherosclerosis and restenosis [3]. However, several studies have recently provided convincing evidence that functional changes in the adventitial compartment also contribute to vascular remodelling during atherogeneis, coronary artery bypass vein graft failure and following angioplasty through the activation, differentiation and luminal migration of adventitial fibroblasts, thereby contributing to neointima formation [4–6]. Several processes and pro-inflammatory factors have been proposed to act locally to contribute to the activation of the adventitial compartment, ranging from enhanced growth factor activity [7] and increased extracellular matrix synthesis [8] to generation of reactive oxygen species [9] and accumulation of progenitor cells [10].

During the response to vascular injury and inflammation, adventitial cells can be reprogrammed to differentiate into different phenotypes. In models of balloon injury, perivascular fibroblasts can be converted into ‘smooth muscle’-like cells, having a migratory myofibroblast phenotype [4–6,11,12]. Both adventitial myofibroblasts, and smooth muscle cells (SMC) in the medial and intimal layers are able to undergo functional and structural changes following vascular injury [13,14], reminiscent of both tissue repair processes and vascular morphogenesis during development. Given the recent studies demonstrating that progenitor cells in the adventitia contribute to the progression of atherosclerosis and restenosis [15], it is conceivable that the mechanisms leading to their homing and differentiation are also responsible for the activation and migration of resident adventitial fibroblasts. Therefore, the approach to deliver genes to the perivascular surface of blood vessels to modulate local pro-inflammatory processes responsible for adventitial activation provides a promising therapeutic strategy for vascular diseases. Moreover, perivascular gene transfer maintains the structural integrity of the vessel wall and endothelium, while high concentrations of gene delivery vectors can be maintained over longer periods in the local environment compared to luminal or systemic gene delivery techniques [16]. This brief review of studies that demonstrate the adventitial cell activation in experimental models of vascular disease highlights the potential benefits of perivascular gene transfer to reduce remodelling of the vessel wall in atherosclerosis and restenosis. In particular, we focus on the antagonism of growth factor signalling and modulation of redox state in the adventitia by efficient local gene delivery through an ‘outside-in’ approach to the vessel wall. The consensus in the literature is that this route may represent an effective therapeutic strategy to ameliorate inflammatory responses following vascular injury.


   2. Growth factors in adventitial myofibroblast migration
Top
 Abstract
 1. Introduction
 2. Growth factors in...
3. Perivascular gene transfer...
 4. Role of adventitial...
 5. Adventitial extracellular...
 6. Adventitial oxidative stress...
 7. Antioxidant genes and...
 8. Summary and future...
 References
 
Percutaneous transluminal coronary angioplasty in humans for the treatment coronary artery occlusion often results in restenosis, affecting more than 30% of patients who undergo balloon angioplasty without stenting. The processes leading to restenosis are similar to those that contribute to accelerated atherosclerosis and vein graft failure after coronary artery bypass surgery [17,18]. Experimental vascular injury in animal models and angioplasty in humans result in migratory and proliferative responses of SMC within the vessel wall in addition to matrix remodelling, characteristic events observed in restenosis and atherosclerosis [17]. Over the past decade, the roles of transforming growth factor-β1 (TGF-β1) and platelet-derived growth factor BB-chain (PDGF-BB) in SMC migration and proliferation have been well characterised in atherogenesis and vascular remodelling following angioplasty in humans and models of arterial injury in animals [19,20]. Antagonism of vascular PDGF-BB signaling, through its sequestration by specific antibodies or inhibition of PDGF β-receptor kinase activity, has been demonstrated to limit vascular remodelling after balloon angioplasty in rats [21–23]. Similarly, removal of TGF-β1 or blockade of its actions in the vessel wall have also been shown to reduce neointimal hyperplasia and loss of lumen diameter following experimental vascular injury in rodent models [24–26]. These studies employed either systemic delivery of neutralising antibodies against the growth factors [21,25] or adenoviral gene delivery systemically or through the arterial lumen using vectors co-ordinating expression of soluble receptors to either PDGF-BB [23] or TGF-β1 [24,26]. More recently, connective tissue growth factor (CTGF) has also been implicated in enhanced adventitial myofibroblast activation and migration in a rabbit vein graft model of vascular remodelling [27] and may thus act as an additional profibrotic perivascular growth factor in synergism with TGF-β1 in the adventitia [28]. In a similar manner, vascular endothelial growth factor (VEGF) can enhance the activity of PDGF-BB to induce SMC migration and proliferation in vascular remodelling [29] and therefore represents another potential perivascular gene target.

By employing a perivascular adenoviral gene delivery technique to specifically label endogenous adventitial cells with the marker gene β-galactosidase prior to vascular injury, we have provided additional evidence to demonstrate that the phenotypic modulation and migration of adventitial myofibroblasts do contribute to neointima formation and vascular remodelling in the rat carotid artery at 7 to 14 days following balloon angioplasty [12]. Previous studies showing migration of adventitial cells in porcine coronary [6] and rat [30] carotid arteries have employed indirect techniques based on labelling cells in a replicative cycle with bromodeoxyuridine which does not specifically identify cells solely of adventitial origin. Although Li et al. [5] attempted to overcome this by seeding exogenous fibroblasts on to the perivascular surface of rat carotid arteries following endoluminal injury, cells observed migrating towards the lumen would have been culture expanded and transfected in vitro using retroviruses to express β-galactosidase, a process likely to have activated and induced phenotypic modulation of the myofibroblasts [31], prior to their reintroduction in different animals, thereby making them more likely to migrate. Therefore, our approach of only labelling resident adventitial fibroblasts in vivo by perivascular gene transfer [12] represents an efficient method of tracking the migration and phenotypic modulation of adventitial cells for over 14 days and moreover, potentially facilitates delivery of transgenes to the medial and neointimal compartments of the vessel wall through luminal migration of transfected adventitial cells following angioplasty.

A similar observation can be made of the recent study by Hu et al. [32] in which progenitor cells expressing stem cell antigen-1 (Sca-1) were isolated from the adventitia of aortic arches and roots from mice, culture expanded and differentiated in vitro by treatment with PDGF-BB for 3 days prior to transfer on to the adventitial surface of vena cava, which were then grafted on to donor mouse carotid arteries. As it has been reported that progenitor cells cultured in growth factor-enriched media can exhibit specific SMC markers such as {alpha}-smooth muscle actin, myosin heavy chain and calponin [33,34], it is likely that in vitro culture and expansion of progenitor cells prior to transplantation results in their differentiation towards a myofibroblast phenotype. Although this may account for some of the findings by Hu et al. [32], where cultured progenitor cells were transferred to the adventitia of vein grafts leading to their migration and neointimal hyperplasia, nevertheless the study highlights the exciting possibility that homing, differentiation and migration of circulating progenitor cells can be influenced by activity of growth factors within the adventitial microenvironment, thereby making the adventitial population of stem cells a novel target for vascular therapeutics to modulate their maturation [35]. Additionally, adventitial progenitor cells may also be used as ‘vehicles’ for vascular gene transfer to the media and neointima through their migration, [36] to attenuate remodelling and the progression of atherogenesis and restenosis [15].


   3. Perivascular gene transfer to antagonise growth factor signalling
Top
 Abstract
 1. Introduction
 2. Growth factors in...
 3. Perivascular gene transfer...
4. Role of adventitial...
 5. Adventitial extracellular...
 6. Adventitial oxidative stress...
 7. Antioxidant genes and...
 8. Summary and future...
 References
 
Our studies have employed perivascular adenoviral gene transfer strategies to locally antagonise either TGF-β1 [37] or PDGF-BB [38] signalling in the adventitial compartment prior to vascular injury involving balloon catheter mediated endothelial denudation and mechanical stretch of rat common carotid arteries. Both growth factors have been established as key mediators involved in fibroblast and SMC phenotypic modulation, migration and hyperplasia in the pathogenesis of atherosclerosis and restenosis [17,18], however a paucity of information exists on their local actions on fibroblasts or progenitor cells in the adventitia. TGF-β1 mediated signalling in the adventitia was attenuated through inhibition of the ‘mothers against decapentaplegic homologues’ (Smad) signalling pathway by adenoviral gene transfer of Smad7 (AdSmad7), the endogenous inhibitor of TGF-β type II receptor mediated Smad2 phosphorylation [39], an early event in the classical TGF-β1 signalling cascade [40,41]. Antagonism of PDGF-BB signalling in the adventitia was achieved by perivascular gene transfer using an adenoviral vector coordinating expression of the soluble extracellular region of the PDGF β-receptor (AdPDGFXR), which has been shown to bind PDGF-BB with high affinity, but not PDGF-AA, and thereby acts as a selective antagonist [42]. Our approach to determine whether growth factor antagonism in the adventitia altered the migration and phenotypic modulation of fibroblasts involved co-delivery to the perivascular surface of an adenovirus co-ordinating expression of the marker transgene β-galactosidase together with either the AdSmad7 or AdPDGFXR vectors 4 days prior to vascular injury. We demonstrated that adventitial transgene expression was maintained for at least 14 days and that local antagonism of either TGF-β1 [37] or PDGF-BB [38] attenuated adventitial cell migration to the media and neointima (Fig. 1), diminished neointimal hyperplasia and constrictive remodelling after angioplasty. Overexpression of both transgenes was associated with a decrease in the transition of adventitial cells to a SMC phenotype and deposition perivascular collagen following vascular balloon injury. However, it is possible that by restricting Smad7 or PDGFXR gene transfer to the adventitia in this study, the contribution of medial SMC proliferation to neointimal hyperplasia remained unaffected. Nevertheless, our studies and others summarised in Table 1 provide direct evidence that adventitial cells play a significant role in vascular remodelling processes under the influence of these growth factors and that perivascular gene transfer is effective in locally antagonising the effects of TGF-β1 or PDGF-BB on fibroblast activation. (Fig. 2).


Figure 1
View larger version (22K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Perivascular gene transfer of Smad7 or PDGFXR reduces adventitial myofibrobalst migration to the neointima following balloon angioplasty. To assess adventitial cell migration, adenoviral pairs encoding expression of the inactive control marker genes β-galactosidase (Adβ-gal) and green fluorescent protein (AdGFP), Adβ-gal and Smad7 (AdSmad7) or Adβ-gal and soluble extracellular region of the human PDGF β-receptor (AdPDGFXR), were suspended in pluronic gel (each at 1010 pfu/ml) and applied to the perivascular adventitial surface of rat common carotid arteries. Four days following gene transfer, balloon catheter injury was performed in transfected carotid arteries to elicit endothelial denudation and arterial distension. Localisation of blue β-galactosidase (β-gal) positive nuclei of adventitial cells contributing to the medial and neointimal compartments were visualised following X-gal staining in sections excised at 3, 7 or 14 days after balloon injury and the proportion of β-gal positive nuclei in the neointimal compartment were quantified using chromagen separation PC software in photomicrographs of AdGFP and Adβ-gal (hatched bars) or AdSmad7 and Adβ-gal (A, solid bars) or AdPDGFXR and Adβ-gal (B, solid bars) transfected carotid artery sections. Data adapted from references 35 and 36 and represent mean±SEM, n=6–12 animals per treatment time point, *p<0.05.

 

View this table:
[in this window]
[in a new window]

  		Table 1 Effects of perivascular gene/progenitor cell transfer on vascular remodelling

 

Figure 2
View larger version (24K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Schematic diagram depicting activation of and migration of adventitial cells during restenosis or vein graft failure. Adventitial cell migration is initially under the influence of perivascular TGF-β1 or PDGF-BB which elicits phenotypic modulation of adventitial fibroblasts or progenitor cells to myofibroblasts and mediates their migration towards the lumen with concomitant increases in matrix metalloproteinase (MMP) expression, collagen deposition and generation of reactive oxygen species (ROS) leading to neointimal hyperplasia and loss of luminal area. Perivascular adenoviral gene transfer to overexpress Smad7 (AdSmad7) or the soluble truncated PDGF β-receptor (AdPDGFXR) antagonises TGF-β1 or PDGF-BB signalling in the adventitial compartment respectively resulting in attenuation of adventitial fibroblast or progenitor cell migration, decreases MMP expression collagen deposition and ROS generation, thereby attenuating intimal thickening and loss of luminal area following vascular injury or vein graft failure. Perivascular gene transfer of endogenous antioxidant defence genes reduces ROS/oxidative stress-mediated adventitial cell activation and migration.

 

   4. Role of adventitial progenitor cells in vascular remodelling
Top
 Abstract
 1. Introduction
 2. Growth factors in...
 3. Perivascular gene transfer...
 4. Role of adventitial...
5. Adventitial extracellular...
 6. Adventitial oxidative stress...
 7. Antioxidant genes and...
 8. Summary and future...
 References
 
It is entirely conceivable that perivascular gene transfer strategies would also diminish the homing and maturation of progenitor cells in the adventitia to a myofibroblastic phenotype since both TGF-β1 and PDGF-BB have been reported to be involved in the differentiation of human multipotent adult progenitor cells into functional SMC or myofibroblasts capable of enhancing the adventitial contribution to neointimal hyperplasia in vascular diseases [15,32,43–45]. It is also possible that adventitial progenitor cells may additionally differentiate either into pericytes [46] or endothelial cells [47] under the influence of TGF-β1, PDGF-BB or VEGF, which in turn, are likely to enhance perivascular angiogenesis [48]. It is possible that progenitor cells are either resident within the adventitia and/or recruited to the vessel wall under the influence of inflammatory cytokines and growth factors and the mechanisms involved in progenitor cell homing and differentiation have already been extensively reviewed elsewhere [15,44,47,49]. In the context of atherosclerotic plaque progression, neovascularization of the lesion, predominantly thought to arise from the adventitia where there are abundant existing vasa vasorum, contributes to intraplaque hemorrhage in advanced lesions which promotes plaque destabilisation and rupture [50]. The importance of angiogenesis is dependent on the stage of lesion development, being a trigger in the early phase and receding within advanced lesions. Khurana et al. [51] demonstrated that adventitial angiogenesis can augment neointima formation in both the rabbit collar and rat angioplasty models of carotid artery injury. In this study, perivascular gene transfer of an adenoviral vector encoding a dominant-negative fibroblast growth factor (FGF) receptor-1 significantly attenuated adventitial angiogenesis in response to vascular injury. Interestingly, liposome mediated adventitial VEGF gene transfer inhibited carotid artery perivascular collar-induced neointimal hyperplasia, macrophage accumulation, and VCAM-1 expression without a significant increase in adventitial neovascularization in a high cholesterol rabbit model of atherosclerosis [52]. In a porcine model of coronary artery angioplasty, liposomal VEGF gene transfer to the periadventitial space resulted in reduced lumen loss due to positive remodelling, prevention of adventitial microvessel regression, enhanced adventitial elastin accumulation and reduced adventitial myofibroblast numbers at 14–28 days after injury [53]. However, the study also reported a pronounced adventitial inflammatory response which may constitute arterial ‘healing’ and thus may be detrimental to perivascular remodelling, activation of myofibroblasts and cytokine generation in the long term.

In addition, the supply of oxygen and entry of inflammatory mediators such as macrophages and oxidized lipoproteins through microvessels within the adventitial compartment are important in both the progression and regression of atherosclerotic and restenotic lesions following intimal and medial hyperplasia [54]. It has been demonstrated that circulating progenitor cells not only promote endothelialization of porcine vein grafts, but also stimulate neointimal hyperplasia, suggesting that they can act simultaneously to suppress remodelling through endothelial repair but also enhance neointimal formation through differentiation into myofibroblasts in vascular diseases [55]. Identification of the homing mechanisms responsible for recruitment of progenitor cells to the adventitia of damaged vessels leading to their differentiation into myofibroblasts or promotion of angiogenesis within the vessel wall would be necessary to develop therapeutic approaches for targeting these processes. Therefore, formation of vasa vasorum–derived adventitial microvessels are an integral component of vascular disease progression [56]. Whilst the exact mechanisms by which TGF-β1, PDGF-BB, FGF and VEGF act alone or in synergy to promote perivascular neovascularisation in addition to cell migration remain to be fully elucidated, it is conceivable that perivascular gene transfer strategies can be employed to either specifically promote or inhibit angiogenic processes locally in the adventitia.


   5. Adventitial extracellular matrix and vascular remodelling
Top
 Abstract
 1. Introduction
 2. Growth factors in...
 3. Perivascular gene transfer...
 4. Role of adventitial...
 5. Adventitial extracellular...
6. Adventitial oxidative stress...
 7. Antioxidant genes and...
 8. Summary and future...
 References
 
An imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) contributes to vessel remodelling in restenosis [57,58]. This may be mediated in part by facilitation of adventitial cell migration through degradation extracellular matrix proteins by enhanced MMP activity and decreased TIMP expression [57]. It has been shown that perivascular adenoviral gene delivery of TIMP-2 to the adventitial surface of mouse vena cava grafted on to mouse common carotid arteries inhibits MMP activity and significantly reduces graft neointimal hyperplasia at 2 to 4 weeks after grafting [59], while non-viral perivascular delivery of TIMP-1 plasmid DNA using lipofectin and integrin-targeting peptides reduced constrictive remodelling of rat carotid arteries at 14 and 28 days following angioplasty [60]. Antagonism of PDGF-BB or TGF-β1 activities in our studies by perivascular AdPDGFXR or AdSmad7 gene transfer respectively, diminished MMP-2 and enhanced TIMP-1 and TIMP-2 expression in the adventitial and medial compartments of balloon injured arteries and decreased collagen deposition [37,38]. Through their regulation of extracellular matrix degradation, MMPs and TIMPs are additional mediators of adventitial myofibroblast and progenitor cell migration through the vessel wall and the contribution of advential cells to vascular remodelling in atherosclerosis and restenosis [57,58]. Modulation of MMP/TIMP expression through perivascular PDGFXR or Smad7 gene transfer may partially account for the attenuation of adventitial cell invasion towards the lumen observed in our studies [37,38] following rat carotid artery balloon injury since both PDGF-BB and TGF-β1 have also been shown to alter MMP and TIMP expression in cultured vascular SMC [61] and fibroblasts [62] respectively. Modulation of adventitial MMP/TIMP activity directly or through antagonism of growth factor signalling by perivascular gene transfer represents a potential strategy to limit remodelling in vascular diseases.


   6. Adventitial oxidative stress and vascular remodelling
Top
 Abstract
 1. Introduction
 2. Growth factors in...
 3. Perivascular gene transfer...
 4. Role of adventitial...
 5. Adventitial extracellular...
 6. Adventitial oxidative stress...
7. Antioxidant genes and...
 8. Summary and future...
 References
 
Far from being an ‘inert’ compartment of the vessel wall, adventitial fibroblasts have been shown to be an source of reactive oxygen species (ROS) in blood vessels following mechanical stretch and injury [9,63]. The literature covering the generation and actions of ROS in the pathogenesis of vascular diseases and angiogenesis has been extensively reviewed elsewhere [64–67]. Although it has been established that balloon angioplasty in rabbit [68], porcine [63] and rat [9,69] models of vascular injury results in redox imbalance, there remains a paucity of reports relating to the contribution of adventitial sources of ROS and the benefits of antioxidant gene expression in vascular remodelling. Superoxide, generated by NAD(P)H oxidase in response to angiotensin II (10 pM) in the adventitia of wild-type but not NAD(P)H oxidase subunit gp91phox deficient mouse aortas, has been shown to contribute to impaired endothelium-derived nitric oxide (NO)-dependent relaxation which was reversed by local adventitial application of superoxide dismutase (SOD) [70]. In this context, perivascular gene delivery of an adenovirus encoding endothelial nitric oxide synthase (eNOS) in canine arteries resulted in adventitial fibroblast NO generation [71] which would beneficially restore vascular reactivity in arteries exhibiting diminished endothelial function [72]. Specific inhibition of adventitial NAD(P)H oxidase activity by perivascular gene transfer using an adenoviral vector encoding gp91ds, a peptide inhibitor driven by the PDGF-β receptor promoter targeted to fibroblasts and interfering with the interaction between NAD(P)H oxidase subunits gp91phox and p47phox, has been demonstrated to reduce vascular superoxide generation and neointima formation in rat and mouse carotid arteries 14 days after balloon angioplasty [73,74].

It is noteworthy that PDGF-BB has been shown not only to enhance superoxide generation in cultured vascular SMC via NAD(P)H oxidase activity [75], but it also modulates expression of peroxiredoxin-II, an endogenous hydrogen peroxide scavenging antioxidant gene [76], in a murine model of vascular injury [77], thus providing additional evidence to support an additional ‘pro-oxidant’ potential of adventitial PDGF-BB signalling in restenosis. Furthermore, TGF-β1 has been recently reported to induce ROS generation and expression of Nox4, an NAD(P)H oxidase homolog, in cultured human arterial SMC through a Smad2 dependent signalling pathway [78]. In addition, the possibility exists that activation of latent TGF-β1 can be directly mediated by ROS, through a redox switch recently identified as a methionine residue at amino acid position 253 [79]. This suggests that latent TGF-β1 sequestered in the adventitial extracellular matrix may be activated not only by increased MMP-2 activity [80] but in addition by enhanced adventitial myofibroblast ROS generation, contributing to augmented perivascular TGF-β1 activity during vascular remodelling [7,37,81].


   7. Antioxidant genes and inhibition of vascular remodelling
Top
 Abstract
 1. Introduction
 2. Growth factors in...
 3. Perivascular gene transfer...
 4. Role of adventitial...
 5. Adventitial extracellular...
 6. Adventitial oxidative stress...
 7. Antioxidant genes and...
8. Summary and future...
 References
 
Given that growth factors can additionally elicit ROS generation by vascular cells [75,78], experimental models of restenosis and bypass graft failure suggest that antioxidant therapies can also be effective to ameliorate vascular remodelling [82,83]. The dietary antioxidant vitamin E has been reported to significantly reduce neointimal thickening in response to balloon injury in rat carotid arteries [84], while more recently, the antioxidants N-acetyl-cysteine and tempol have been demonstrated to reduce PDGF β-receptor activation by enhancing protein tyrosine phosphatase (PTP) activity, thereby attenuating proliferation and migration of rat aortic SMC in vitro and reducing neointima formation following angioplasty in rat carotid arteries [69]. This implies that PTP modulation by ROS may augment PDGF-BB signalling which would consequently further augment the contribution of adventitial myofibroblasts to vascular remodelling. Considering the extensive evidence that oxidative modifications are intimately involved in vascular diseases and the controversy surrounding the limited benefits of dietary antioxidant interventions in human studies [85], in the context of adventitial oxidative stress, an alternative therapeutic strategy may be to locally transfer protective endogenous antioxidant genes to modulate perivascular redox status. Gene transfer studies by direct vector injection to the vessel wall of adenoviruses encoding superoxide dismutase and catalase have been shown to improve endothelial function, reduce ROS generation and restenosis following iliac artery angioplasty in a rabbit model of atherosclerosis [86]. This was likely to have counteracted the decreased arterial activity of SOD observed to be associated with constrictive remodelling in a rabbit model of vascular injury [87]. Recently Levonen et al. [88] reported that luminal gene transfer with an adenoviral vector coordinating expression of the transcription factor nuclear factor E2-related factor (Nrf2) reduces oxidative stress and inflammation in the vessel wall at 14 days following balloon angioplasty in rabbit aortas. Nrf2 is the key transcription factor that regulates concerted induction of several antioxidant enzymes such as heme oxygenase-1 (HO-1) [89,90], which exhibits anti-atherogenic properties by virtue of its key role in catabolising the pro-oxidant heme to generate the vasodilator carbon monoxide (CO) and lipid peroxide scavenging antioxidant biliverdin [91,92]. In the context of vascular remodelling, local adenoviral HO-1 gene transfer or administration of CO or biliverdin have been shown to reduce neointimal hyperplasia following experimental vascular balloon injury or vein graft arterialisation in rats [93–95]. Interestingly, the anti-restenotic properties of the antioxidant drug probucol have also been attributed to vascular HO-1 induction following endothelial denudation of rabbit aortas [96]. In addition, it is conceivable that enhanced adventitial ROS generation may further act to augment differentiation of progenitor cells toward a myofibroblastic phenotype which can contribute to neointimal hyperplasia [97]. Taken together, it is likely that further research to evaluate perivascular gene transfer to antagonise growth factor signalling, inhibit NAD(P)H oxidase activation and enhance expression of endogenous antioxidant defence genes will yield novel therapeutic strategies to modulate redox signalling pathways that reduce adventitial activation and vascular remodelling in atherosclerosis and following angioplasty.


   8. Summary and future perspectives
Top
 Abstract
 1. Introduction
 2. Growth factors in...
 3. Perivascular gene transfer...
 4. Role of adventitial...
 5. Adventitial extracellular...
 6. Adventitial oxidative stress...
 7. Antioxidant genes and...
 8. Summary and future...
References
 
The potential benefits of vascular gene transfer as a research tool and potential therapeutic strategy for cardiovascular disease have been well documented over the past decade [98,99]. In particular, perivascular gene delivery from the ‘outside-in’ through the adventitia may be advantageous by virtue that it can be performed by direct application of vectors during surgical procedures that yields localised transgene expression in the adventitial compartment with fewer pro-inflammatory effects compared to intraluminal gene delivery [16,100,101]. Currently only about 5% of percutaneous interventional angioplasty procedures in developed countries are performed without stent implantation, however, although restenosis without stenting has become a relatively minor clinical problem, the pro-inflammatory mechanisms underlying in-stent restenosis as well as vein graft failure similarly involve enhanced growth factor signalling, ROS generation and stem cell differentiation leading to adventitial cell activation and neointimal hyperplasia [19,102–104]. However, for successful clinical implementation of perivascular gene therapy, larger trials remain to be performed and long term safety and efficacy considerations of utilising a variety of viral and non-viral therapeutic vectors must be further addressed for in-stent restenosis and vein graft failure [105,106]. The biological activity of overexpressed transgenes delivered to the vessel wall should also be treated with caution in the context of the disease model. For example, eNOS gene delivery to the adventitia [71] may result in uncoupling of the enzyme to generate deleterious superoxide under certain conditions [107]. Furthermore, strategies to modulate perivascular TGF-β1 activity [24,26,37] may lead to advanced atherosclerotic plaque destabilisation [108], and vascular VEGF gene transfer [52] may lead to plaque neovascularisation, haemorrhage and expansion [109]. Nevertheless, this review has highlighted the promise of efficient adventitial gene delivery to modulate fibroblast and progenitor cell growth factor and redox signalling pathways as an important experimental tool to provide further mechanistic insights for clinical perivascular therapy approaches to reduce the incidence of restenosis following angioplasty, stent implantation and coronary artery bypass grafting. It is possible that gene delivery to the adventitia following angioplasty and bypass procedures through use of coated drug-eluting perivascular stent cuffs [110,111] may represent a future clinical strategy for the reduction in the incidence of restenosis and vein graft failure.

Time for primary review 24 days


   Acknowledgements
 
Studies performed by the authors as cited in this review were supported by the British Heart Foundation. Dr Adrian Churchman is a British Heart Foundation funded postdoctoral research associate. We are very grateful to Professor Giovanni Mann, Cardiovascular Division, King's College London, for helpful scientific discussion and encouragement during the preparation of this review.


   References
Top
 Abstract
 1. Introduction
 2. Growth factors in...
 3. Perivascular gene transfer...
 4. Role of adventitial...
 5. Adventitial extracellular...
 6. Adventitial oxidative stress...
 7. Antioxidant genes and...
 8. Summary and future...
 References
 

  1. Sartore S., Chiavegato A., Faggin E., Franch R., Puato M., Ausoni S., et al. Contribution of adventitial fibroblasts to neointima formation and vascular remodeling: from innocent bystander to active participant. Circ Res (2001) 89:1111–1121.[Abstract/Free Full Text]
  2. Shi Y., Pieniek M., Fard A., O'Brien J., Mannion J.D., Zalewski A. Adventitial remodeling after coronary arterial injury. Circulation (1996) 93:340–348.[Abstract/Free Full Text]
  3. Schwartz S.M., deBlois D., O'Brien E.R. The intima. Soil for atherosclerosis and restenosis. Circ Res (1995) 77:445–465.[Free Full Text]
  4. Zalewski A., Shi Y. Vascular myofibroblasts. Lessons from coronary repair and remodeling. Arterioscler Thromb Vasc Biol (1997) 17:417–422.[Free Full Text]
  5. Li G., Chen S.J., Oparil S., Chen Y.F., Thompson J.A. Direct in vivo evidence demonstrating neointimal migration of adventitial fibroblasts after balloon injury of rat carotid arteries. Circulation (2000) 101:1362–1365.[Abstract/Free Full Text]
  6. Shi Y., O'Brien J.E., Fard A., Mannion J.D., Wang D., Zalewski A. Adventitial myofibroblasts contribute to neointimal formation in injured porcine coronary arteries. Circulation (1996) 94:1655–1664.[Abstract/Free Full Text]
  7. Shi Y., O'Brien J.E. Jr., Fard A., Zalewski A. Transforming growth factor-beta 1 expression and myofibroblast formation during arterial repair. Arterioscler Thromb Vasc Biol (1996) 16:1298–1305.[Abstract/Free Full Text]
  8. Shi Y., O'Brien J.E. Jr., la-Kokko L., Chung W., Mannion J.D., Zalewski A. Origin of extracellular matrix synthesis during coronary repair. Circulation (1997) 95:997–1006.[Abstract/Free Full Text]
  9. Rey F.E., Pagano P.J. The reactive adventitia: fibroblast oxidase in vascular function. Arterioscler Thromb Vasc Biol (2002) 22:1962–1971.[Abstract/Free Full Text]
  10. Torsney E., Hu Y., Xu Q. Adventitial progenitor cells contribute to arteriosclerosis. Trends Cardiovasc Med (2005) 15:64–68.[CrossRef][Web of Science][Medline]
  11. Faggin E., Puato M., Zardo L., Franch R., Millino C., Sarinella F., et al. Smooth muscle-specific SM22 protein is expressed in the adventitial cells of balloon-injured rabbit carotid artery. Arterioscler Thromb Vasc Biol (1999) 19:1393–1404.[Abstract/Free Full Text]
  12. Siow R.C., Mallawaarachchi C.M., Weissberg P.L. Migration of adventitial myofibroblasts following vascular balloon injury: insights from in vivo gene transfer to rat carotid arteries. Cardiovasc Res (2003) 59:212–221.[Abstract/Free Full Text]
  13. Couffinhal T., Dufourcq P., Jaspard B., Daret D., Allieres C., Alzieu P., et al. Kinetics of adventitial repair in the rat carotid model. Coron Artery Dis (2001) 12:635–648.[CrossRef][Web of Science][Medline]
  14. Christen T., Verin V., Bochaton-Piallat M., Popowski Y., Ramaekers F., Debruyne P., et al. Mechanisms of neointima formation and remodeling in the porcine coronary artery. Circulation (2001) 103:882–888.[Abstract/Free Full Text]
  15. Xu Q. The impact of progenitor cells in atherosclerosis. Nat Clin Pract Cardiovasc Med (2006) 3:94–101.[CrossRef][Web of Science][Medline]
  16. Laitinen M., Yla-Herttuala S. Adventitial gene transfer to arterial wall. Pharmacol Res (1998) 37:251–254.[CrossRef][Web of Science][Medline]
  17. Schwartz S.M. Smooth muscle migration in atherosclerosis and restenosis. J Clin Invest (1997) 100:S87–S89.[Web of Science][Medline]
  18. Ross R. Atherosclerosis’an inflammatory disease. N Engl J Med (1999) 340:115–126.[Free Full Text]
  19. Khan R., Agrotis A., Bobik A. Understanding the role of transforming growth factor-beta1 in intimal thickening after vascular injury. Cardiovasc Res (2007) 74:223–234.[Abstract/Free Full Text]
  20. Lindner V., Giachelli C.M., Schwartz S.M., Reidy M.A. A subpopulation of smooth muscle cells in injured rat arteries expresses platelet-derived growth factor-B chain mRNA. Circ Res (1995) 76:951–957.[Abstract/Free Full Text]
  21. Levitzki A. PDGF receptor kinase inhibitors for the treatment of restenosis. Cardiovasc Res (2005) 65:581–586.[Abstract/Free Full Text]
  22. Ferns G.A., Raines E.W., Sprugel K.H., Motani A.S., Reidy M.A., Ross R. Inhibition of neointimal smooth muscle accumulation after angioplasty by an antibody to PDGF. Science (1991) 253:1129–1132.[Abstract/Free Full Text]
  23. Deguchi J., Namba T., Hamada H., Nakaoka T., Abe J., Sato O., et al. Targeting endogenous platelet-derived growth factor B-chain by adenovirus-mediated gene transfer potently inhibits in vivo smooth muscle proliferation after arterial injury. Gene Ther (1999) 6:956–965.[CrossRef][Web of Science][Medline]
  24. Kingston P.A., Sinha S., David A., Castro M.G., Lowenstein P.R., Heagerty A.M. Adenovirus-mediated gene transfer of a secreted transforming growth factor-beta type II receptor inhibits luminal loss and constrictive remodeling after coronary angioplasty and enhances adventitial collagen deposition. Circulation (2001) 104:2595–2601.[Abstract/Free Full Text]
  25. Wolf Y.G., Rasmussen L.M., Ruoslahti E. Antibodies against transforming growth factor-beta 1 suppress intimal hyperplasia in a rat model. J Clin Invest (1994) 93:1172–1178.[Web of Science][Medline]
  26. Smith J.D., Bryant S.R., Couper L.L., Vary C.P., Gotwals P.J., Koteliansky V.E., et al. Soluble transforming growth factor-beta type II receptor inhibits negative remodeling, fibroblast transdifferentiation, and intimal lesion formation but not endothelial growth. Circ Res (1999) 84:1212–1222.[Abstract/Free Full Text]
  27. Jiang Z., Yu P., Tao M., Fernandez C., Ifantides C., Moloye O., et al. TGF-beta/CTGF mediated fibroblast recruitment influences early outward vein graft remodeling. Am J Physiol Heart Circ Physiol (2007) 10.1152/ajpheart.01372.2006.
  28. Leask A., Abraham D.J. The role of connective tissue growth factor, a multifunctional matricellular protein in fibroblast biology. Biochem Cell Biol (2003) 81:355–363.[CrossRef][Web of Science][Medline]
  29. Nykanen A.I., Krebs R., Tikkanen J.M., Raisky O., Sihvola R., Wood J., et al. Combined vascular endothelial growth factor and platelet-derived growth factor inhibition in rat cardiac allografts: beneficial effects on inflammation and smooth muscle cell proliferation. Transplantation (2005) 79:182–189.[CrossRef][Web of Science][Medline]
  30. Oparil S., Chen S.J., Chen Y.F., Durand J.N., Allen L., Thompson J.A. Estrogen attenuates the adventitial contribution to neointima formation in injured rat carotid arteries. Cardiovasc Res (1999) 44:608–614.[Abstract/Free Full Text]
  31. Masur S.K., Dewal H.S., Dinh T.T., Erenburg I., Petridou S. Myofibroblasts differentiate from fibroblasts when plated at low density. Proc Natl Acad Sci U S A (1996) 93:4219–4223.[Abstract/Free Full Text]
  32. Hu Y., Zhang Z., Torsney E., Afzal A.R., Davison F., Metzler B., et al. Abundant progenitor cells in the adventitia contribute to atherosclerosis of vein grafts in ApoE-deficient mice. J Clin Invest (2004) 113:1258–1265.[CrossRef][Web of Science][Medline]
  33. Simper D., Stalboerger P.G., Panetta C.J., Wang S., Caplice N.M. Smooth muscle progenitor cells in human blood. Circulation (2002) 106:1199–1204.[Abstract/Free Full Text]
  34. Lu X., Dunn J., Dickinson A.M., Gillespie J.I., Baudouin S.V. Smooth muscle alpha-actin expression in endothelial cells derived from CD34+ human cord blood cells. Stem Cells Dev (2004) 13:521–527.[Web of Science][Medline]
  35. Sata M., Fukuda D., Tanaka K., Kaneda Y., Yashiro H., Shirakawa I. The role of circulating precursors in vascular repair and lesion formation. J Cell Mol Med (2005) 9:557–568.[Web of Science][Medline]
  36. Pearson J.D. Using endothelial progenitor cells for gene therapy. Arterioscler Thromb Vasc Biol (2003) 23:2117–2118.[Free Full Text]
  37. Mallawaarachchi C.M., Weissberg P.L., Siow R.C. Smad7 gene transfer attenuates adventitial cell migration and vascular remodeling after balloon injury. Arterioscler Thromb Vasc Biol (2005) 25:1383–1387.[Abstract/Free Full Text]
  38. Mallawaarachchi C.M., Weissberg P.L., Siow R.C. Antagonism of platelet-derived growth factor by perivascular gene transfer attenuates adventitial cell migration after vascular injury: new tricks for old dogs? FASEB J (2006) 20:1686–1688.[Abstract/Free Full Text]
  39. Nakao A., Afrakhte M., Moren A., Nakayama T., Christian J.L., Heuchel R., et al. Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature (1997) 389:631–635.[CrossRef][Medline]
  40. Attisano L., Wrana J.L. Signal transduction by the TGF-beta superfamily. Science (2002) 296:1646–1647.[Abstract/Free Full Text]
  41. Ikedo H., Tamaki K., Ueda S., Kato S., Fujii M., Ten D.P., et al. Smad protein and TGF-beta signaling in vascular smooth muscle cells. Int J Mol Med (2003) 11:645–650.[Web of Science][Medline]
  42. Duan D.S., Pazin M.J., Fretto L.J., Williams L.T. A functional soluble extracellular region of the platelet-derived growth factor (PDGF) beta-receptor antagonizes PDGF-stimulated responses. J Biol Chem (1991) 266:413–418.[Abstract/Free Full Text]
  43. Ross J.J., Hong Z., Willenbring B., Zeng L., Isenberg B., Lee E.H., et al. Cytokine-induced differentiation of multipotent adult progenitor cells into functional smooth muscle cells. J Clin Invest (2006) 116:3139–3149.[CrossRef][Web of Science][Medline]
  44. Liu C., Nath K.A., Katusic Z.S., Caplice N.M. Smooth muscle progenitor cells in vascular disease. Trends Cardiovasc Med (2004) 14:288–293.[CrossRef][Web of Science][Medline]
  45. Wilcox J.N., Okamoto E.I., Nakahara K.I., Vinten-Johansen J. Perivascular responses after angioplasty which may contribute to postangioplasty restenosis: a role for circulating myofibroblast precursors? Ann N Y Acad Sci (2001) 947:68–90.[Web of Science][Medline]
  46. Lindskog H., Athley E., Larsson E., Lundin S., Hellstrom M., Lindahl P. New insights to vascular smooth muscle cell and pericyte differentiation of mouse embryonic stem cells in vitro. Arterioscler Thromb Vasc Biol (2006) 26:1457–1464.[Abstract/Free Full Text]
  47. Luttun A., Carmeliet G., Carmeliet P. Vascular progenitors: from biology to treatment. Trends Cardiovasc Med (2002) 12:88–96.[CrossRef][Web of Science][Medline]
  48. Carmeliet P. Angiogenesis in health and disease. Nat Med (2003) 9:653–660.[CrossRef][Web of Science][Medline]
  49. Hristov M., Erl W., Weber P.C. Endothelial progenitor cells: mobilization, differentiation, and homing. Arterioscler Thromb Vasc Biol (2003) 23:1185–1189.[Abstract/Free Full Text]
  50. Virmani R., Kolodgie F.D., Burke A.P., Finn A.V., Gold H.K., Tulenko T.N., et al. Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol (2005) 25:2054–2061.[Abstract/Free Full Text]
  51. Khurana R., Zhuang Z., Bhardwaj S., Murakami M., De M.E., Yla-Herttuala S., et al. Angiogenesis-dependent and independent phases of intimal hyperplasia. Circulation (2004) 110:2436–2443.[Abstract/Free Full Text]
  52. Khurana R., Shafi S., Martin J., Zachary I. Vascular endothelial growth factor gene transfer inhibits neointimal macrophage accumulation in hypercholesterolemic rabbits. Arterioscler Thromb Vasc Biol (2004) 24:1074–1080.[Abstract/Free Full Text]
  53. Deiner C., Schwimmbeck P.L., Koehler I.S., Loddenkemper C., Noutsias M., Nikol S., et al. Adventitial VEGF165 gene transfer prevents lumen loss through induction of positive arterial remodeling after PTCA in porcine coronary arteries. Atherosclerosis (2006) 189:123–132.[CrossRef][Web of Science][Medline]
  54. Moreno P.R., Purushothaman K.R., Sirol M., Levy A.P., Fuster V. Neovascularization in human atherosclerosis. Circulation (2006) 113:2245–2252.[Free Full Text]
  55. Rotmans J.I., Heyligers J.M., Verhagen H.J., Velema E., Nagtegaal M.M., de Kleijn D.P., et al. In vivo cell seeding with anti-CD34 antibodies successfully accelerates endothelialization but stimulates intimal hyperplasia in porcine arteriovenous expanded polytetrafluoroethylene grafts. Circulation (2005) 112:12–18.[Abstract/Free Full Text]
  56. Moulton K.S. Angiogenesis in atherosclerosis: gathering evidence beyond speculation. Curr Opin Lipidol (2006) 17:548–555.[Web of Science][Medline]
  57. Galis Z.S., Khatri J.J. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res (2002) 90:251–262.[Abstract/Free Full Text]
  58. Newby A.C. Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture. Physiol Rev (2005) 85:1–31.[Abstract/Free Full Text]
  59. Hu Y., Baker A.H., Zou Y., Newby A.C., Xu Q. Local gene transfer of tissue inhibitor of metalloproteinase-2 influences vein graft remodeling in a mouse model. Arterioscler Thromb Vasc Biol (2001) 21:1275–1280.[Abstract/Free Full Text]
  60. Meng Q.H., Jamal W., Hart S.L., McEwan J.R. Application to vascular adventitia of a nonviral vector for TIMP-1 gene therapy to prevent intimal hyperplasia. Hum Gene Ther (2006) 17:717–727.[CrossRef][Web of Science][Medline]
  61. Lau H.K. Regulation of proteolytic enzymes and inhibitors in two smooth muscle cell phenotypes. Cardiovasc Res (1999) 43:1049–1059.[Abstract/Free Full Text]
  62. Hall M.C., Young D.A., Waters J.G., Rowan A.D., Chantry A., Edwards D.R., et al. The comparative role of activator protein 1 and Smad factors in the regulation of TIMP-1 and MMP-1 gene expression by transforming growth factor-beta 1. J Biol Chem (2003) 278:10304–10313.[Abstract/Free Full Text]
  63. Shi Y., Niculescu R., Wang D., Patel S., Davenpeck K.L., Zalewski A. Increased NAD(P)H oxidase and reactive oxygen species in coronary arteries after balloon injury. Arterioscler Thromb Vasc Biol (2001) 21:739–745.[Abstract/Free Full Text]
  64. Bedard K., Krause K.H. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev (2007) 87:245–313.[Abstract/Free Full Text]
  65. Cai H., Griendling K.K., Harrison D.G. The vascular NAD(P)H oxidases as therapeutic targets in cardiovascular diseases. Trends Pharmacol Sci (2003) 24:471–478.[CrossRef][Medline]
  66. Ushio-Fukai M., Alexander R.W. Reactive oxygen species as mediators of angiogenesis signaling: role of NAD(P)H oxidase. Mol Cell Biochem (2004) 264:85–97.[CrossRef][Web of Science][Medline]
  67. Griendling K.K., FitzGerald G.A. Oxidative stress and cardiovascular injury: part II: animal and human studies. Circulation (2003) 108:2034–2040.[Free Full Text]
  68. Pollman M.J., Hall J.L., Gibbons G.H. Determinants of vascular smooth muscle cell apoptosis after balloon angioplasty injury. Influence of redox state and cell phenotype. Circ Res (1999) 84:113–121.[Abstract/Free Full Text]
  69. Kappert K., Sparwel J., Sandin A., Seiler A., Siebolts U., Leppanen O., et al. Antioxidants relieve phosphatase inhibition and reduce PDGF signaling in cultured VSMCs and in restenosis. Arterioscler Thromb Vasc Biol (2006) 26:2644–2651.[Abstract/Free Full Text]
  70. Rey F.E., Li X.C., Carretero O.A., Garvin J.L., Pagano P.J. Perivascular superoxide anion contributes to impairment of endothelium-dependent relaxation: role of gp91(phox). Circulation (2002) 106:2497–2502.[Abstract/Free Full Text]
  71. Tsutsui M., Chen A.F., O'Brien T., Crotty T.B., Katusic Z.S. Adventitial expression of recombinant eNOS gene restores NO production in arteries without endothelium. Arterioscler Thromb Vasc Biol (1998) 18:1231–1241.[Abstract/Free Full Text]
  72. Gutterman D.D. Adventitia-dependent influences on vascular function. Am J Physiol (1999) 277:H1265–H1272.[Web of Science][Medline]
  73. Dourron H.M., Jacobson G.M., Park J.L., Liu J., Reddy D.J., Scheel M.L., et al. Perivascular gene transfer of NADPH oxidase inhibitor suppresses angioplasty-induced neointimal proliferation of rat carotid artery. Am J Physiol Heart Circ Physiol (2005) 288:H946–H953.[Abstract/Free Full Text]
  74. Liu J., Ormsby A., Oja-Tebbe N., Pagano P.J. Gene transfer of NAD(P)H oxidase inhibitor to the vascular adventitia attenuates medial smooth muscle hypertrophy. Circ Res (2004) 95:587–594.[Abstract/Free Full Text]
  75. Kreuzer J., Viedt C., Brandes R.P., Seeger F., Rosenkranz A.S., Sauer H., et al. Platelet-derived growth factor activates production of reactive oxygen species by NAD(P)H oxidase in smooth muscle cells through Gi1,2. FASEB J (2003) 17:38–40.[Abstract/Free Full Text]
  76. Rhee S.G., Chae H.Z., Kim K. Peroxiredoxins: a historical overview and speculative preview of novel mechanisms and emerging concepts in cell signaling. Free Radic Biol Med (2005) 38:1543–1552.[CrossRef][Web of Science][Medline]
  77. Choi M.H., Lee I.K., Kim G.W., Kim B.U., Han Y.H., Yu D.Y., et al. Regulation of PDGF signalling and vascular remodelling by peroxiredoxin II. Nature (2005) 435:347–353.[CrossRef][Medline]
  78. Sturrock A., Cahill B., Norman K., Huecksteadt T.P., Hill K., Sanders K., et al. Transforming growth factor-beta1 induces Nox4 NAD(P)H oxidase and reactive oxygen species-dependent proliferation in human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol (2006) 290:L661–L673.[Abstract/Free Full Text]
  79. Jobling M.F., Mott J.D., Finnegan M.T., Jurukovski V., Erickson A.C., Walian P.J., et al. Isoform-specific activation of latent transforming growth factor beta (LTGF-beta) by reactive oxygen species. Radiat Res (2006) 166:839–848.[CrossRef][Web of Science][Medline]
  80. Wang M., Zhao D., Spinetti G., Zhang J., Jiang L.Q., Pintus G., et al. Matrix metalloproteinase 2 activation of transforming growth factor-beta1 (TGF-beta1) and TGF-beta1-type II receptor signaling within the aged arterial wall. Arterioscler Thromb Vasc Biol (2006) 26:1503–1509.[Abstract/Free Full Text]
  81. Lindner V. Vascular repair processes mediated by transforming growth factor-beta. Z Kardiol (2001) 90 Suppl 3:17–22.
  82. Jeremy J.Y., Shukla N., Muzaffar S., Handley A., Angelini G.D. Reactive oxygen species vascular disease and cardiovascular surgery. Curr Vasc Pharmacol (2004) 2:229–236.[CrossRef][Medline]
  83. Tardif J.C., Gregoire J., Lavoie M.A., L'allier P.L. Pharmacologic prevention of both restenosis and atherosclerosis progression: AGI-1067, probucol, statins, folic acid and other therapies. Curr Opin Lipidol (2003) 14:615–620.[CrossRef][Web of Science][Medline]
  84. Konneh M.K., Rutherford C., Li S.R., Anggard E.E., Ferns G.A. Vitamin E inhibits the intimal response to balloon catheter injury in the carotid artery of the cholesterol-fed rat. Atherosclerosis (1995) 113:29–39.[CrossRef][Web of Science][Medline]
  85. Stocker R., Keaney J.F. Jr. Role of oxidative modifications in atherosclerosis. Physiol Rev (2004) 84:1381–1478.[Abstract/Free Full Text]
  86. Durand E., Al Haj Z.A., Addad F., Brasselet C., Caligiuri G., Vinchon F., et al. Adenovirus-mediated gene transfer of superoxide dismutase and catalase decreases restenosis after balloon angioplasty. J Vasc Res (2005) 42:255–265.[CrossRef][Web of Science][Medline]
  87. Leite P.F., Danilovic A., Moriel P., Dantas K., Marklund S., Dantas A.P., et al. Sustained decrease in superoxide dismutase activity underlies constrictive remodeling after balloon injury in rabbits. Arterioscler Thromb Vasc Biol (2003) 23:2197–2202.[Abstract/Free Full Text]
  88. Levonen A.L., Inkala M., Heikura T., Jauhiainen S., Jyrkkanen H.K., Kansanen E., et al. Nrf2 gene transfer induces antioxidant enzymes and suppresses smooth muscle cell growth in vitro and reduces oxidative stress in rabbit aorta in vivo. Arterioscler Thromb Vasc Biol (2007) 27:741–747.[Abstract/Free Full Text]
  89. Motohashi H., Yamamoto M. Nrf2-Keap1 defines a physiologically important stress response mechanism. Trends Mol Med (2004) 10:549–557.[CrossRef][Web of Science][Medline]
  90. Lee J.M., Li J., Johnson D.A., Stein T.D., Kraft A.D., Calkins M.J., et al. Nrf2, a multi-organ protector? FASEB J (2005) 19:1061–1066.[Abstract/Free Full Text]
  91. Siow R.C., Sato H., Mann G.E. Heme oxygenase-carbon monoxide signalling pathway in atherosclerosis: anti-atherogenic actions of bilirubin and carbon monoxide? Cardiovasc Res (1999) 41:385–394.[Abstract/Free Full Text]
  92. Ryter S.W., Alam J., Choi A.M. Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol Rev (2006) 86:583–650.[Abstract/Free Full Text]
  93. Tulis D.A., Durante W., Liu X., Evans A.J., Peyton K.J., Schafer A.I. Adenovirus-mediated heme oxygenase-1 gene delivery inhibits injury-induced vascular neointima formation. Circulation (2001) 104:2710–2715.[Abstract/Free Full Text]
  94. Tulis D.A., Keswani A.N., Peyton K.J., Wang H., Schafer A.I., Durante W. Local administration of carbon monoxide inhibits neointima formation in balloon injured rat carotid arteries. Cell Mol Biol (Noisy -le-grand) (2005) 51:441–446.[Web of Science][Medline]
  95. Nakao A., Murase N., Ho C., Toyokawa H., Billiar T.R., Kanno S. Biliverdin administration prevents the formation of intimal hyperplasia induced by vascular injury. Circulation (2005) 112:587–591.[Abstract/Free Full Text]
  96. Deng Y.M., Wu B.J., Witting P.K., Stocker R. Probucol protects against smooth muscle cell proliferation by upregulating heme oxygenase-1. Circulation (2004) 110:1855–1860.[Abstract/Free Full Text]
  97. Sauer H., Wartenberg M. Reactive oxygen species as signaling molecules in cardiovascular differentiation of embryonic stem cells and tumor-induced angiogenesis. Antioxid Redox Signal (2005) 7:1423–1434.[CrossRef][Web of Science][Medline]
  98. Yla-Herttuala S., Martin J.F. Cardiovascular gene therapy. Lancet (2000) 355:213–222.[CrossRef][Web of Science][Medline]
  99. Khurana R., Martin J.F., Zachary I. Gene therapy for cardiovascular disease: a case for cautious optimism. Hypertension (2001) 1210–1216.
  100. Schneider D.B., Sassani A.B., Vassalli G., Driscoll R.M., Dichek D.A. Adventitial delivery minimizes the proinflammatory effects of adenoviral vectors. J Vasc Surg (1999) 29:543–550.[CrossRef][Web of Science][Medline]
  101. Laitinen M., Pakkanen T., Donetti E., Baetta R., Luoma J., Lehtolainen P., et al. Gene transfer into the carotid artery using an adventitial collar: comparison of the effectiveness of the plasmid-liposome complexes, retroviruses, pseudotyped retroviruses, S and adenoviruses. Hum Gene Ther (1997) 8:1645–1650.[Web of Science][Medline]
  102. Welt F.G., Rogers C. Inflammation and restenosis in the stent era. Arterioscler Thromb Vasc Biol (2002) 22:1769–1776.[Abstract/Free Full Text]
  103. Inoue T., Sata M., Hikichi Y., Sohma R., Fukuda D., Uchida T., et al. Mobilization of CD34-positive bone marrow-derived cells after coronary stent implantation: impact on restenosis. Circulation (2007) 115:553–561.[Abstract/Free Full Text]
  104. Ohtani K., Egashira K., Ihara Y., Nakano K., Funakoshi K., Zhao G., et al. Angiotensin II type 1 receptor blockade attenuates in-stent restenosis by inhibiting inflammation and progenitor cells. Hypertension (2006) 48:664–670.[Abstract/Free Full Text]
  105. Isner J.M., Vale P.R., Symes J.F., Losordo D.W. Assessment of risks associated with cardiovascular gene therapy in human subjects. Circ Res (2001) 89:389–400.[Abstract/Free Full Text]
  106. Dzau V.J., Beatt K., Pompilio G., Smith K. Current perceptions of cardiovascular gene therapy. Am J Cardiol (2003) 92:18N–23N.[Web of Science][Medline]
  107. Forstermann U., Munzel T. Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation (2006) 113:1708–1714.[Abstract/Free Full Text]
  108. Mallat Z., Tedgui A. The role of transforming growth factor beta in atherosclerosis: novel insights and future perspectives. Curr Opin Lipidol (2002) 13:523–529.[CrossRef][Web of Science][Medline]
  109. Moulton K.S. Angiogenesis in atherosclerosis: gathering evidence beyond speculation. Curr Opin Lipidol (2006) 17:548–555.[Web of Science][Medline]
  110. Pires N.M., van der Hoeven B.L., de Vries M.R., Havekes L.M., van Vlijmen B.J., Hennink W.E., et al. Local perivascular delivery of anti-restenotic agents from a drug-eluting poly(epsilon-caprolactone) stent cuff. Biomaterials (2005) 26:5386–5394.[CrossRef][Web of Science][Medline]
  111. Jeremy J.Y., Gadsdon P., Shukla N., Vijayan V., Wyatt M., Newby A.C., et al. On the biology of saphenous vein grafts fitted with external synthetic sheaths and stents. Biomaterials (2007) 28:895–908.[CrossRef][Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Proc Am Thorac SocHome page
T. Stevens, S. Phan, M. G. Frid, D. Alvarez, E. Herzog, and K. R. Stenmark
Lung Vascular Cell Heterogeneity: Endothelium, Smooth Muscle, and Fibroblasts
Proceedings of the ATS, September 15, 2008; 5(7): 783 - 791.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
F. Feihl, L. Liaudet, B. I. Levy, and B. Waeber
Hypertension and microvascular remodelling
Cardiovasc Res, May 1, 2008; 78(2): 274 - 285.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
P. J. Pagano and D. D. Gutterman
The adventitia: The outs and ins of vascular disease
Cardiovasc Res, September 1, 2007; 75(4): 636 - 639.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Siow, R. C.M.
Right arrow Articles by Churchman, A. T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Siow, R. C.M.
Right arrow Articles by Churchman, A. T.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?