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Cardiovascular Research 2000 45(4):843-852; doi:10.1016/S0008-6363(99)00377-6
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Copyright © 2000, European Society of Cardiology

Arterial remodeling in atherosclerosis, restenosis and after alteration of blood flow: potential mechanisms and clinical implications

Gerard Pasterkampa,*, Dominique P.V de Kleijna and Cornelius Borstb

aInteruniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands
bExperimental Cardiology Laboratory, Utrecht University Medical Center, Utrecht, The Netherlands

* Corresponding author. Correspondence address: Heart Lung Institute, Utrecht University Hospital, Heidelberglaan 100, Room G02.523, 3584 CX Utrecht, The Netherlands. Tel.: +31-30-250-7155; fax: +31-30-252-2693 g.pasterkamp{at}hli.azu.nl

Received 21 July 1999; accepted 18 October 1999


   Abstract
Top
 Abstract
1 Introduction
 2 Arterial remodeling: new...
 3 Mechanisms of arterial...
 4 Limitations in the...
 5 Future perspectives: search...
 6 Conclusions
 References
 
Arterial remodeling is currently being recognized as an important determinant in vascular pathology in which narrowing of the lumen is the predominant feature. Not only expansive remodeling (enlargement), but also constrictive remodeling (shrinkage) is observed in de novo atherosclerosis, in restenosis and in transplant vasculopathy. Expansive remodeling prevents and constrictive remodeling enhances luminal narrowing by plaque formation or intimal hyperplasia. The mechanisms of the opposite remodeling modes is unknown. Insight into the processes that determine the direction of local arterial remodeling may help to develop new strategies to prevent arterial occlusive disease. In the present paper the current status of research in the field of arterial remodeling in cardiovascular disease is reviewed. Mechanisms of arterial remodeling, potential interventions to influence the mode of remodeling as well as the methodological limitations of remodeling studies are discussed.

KEYWORDS Angioplasty; Arteries; Artherosclerosis; Blood flow; Remodeling; Restenosis


   1 Introduction
Top
 Abstract
 1 Introduction
2 Arterial remodeling: new...
 3 Mechanisms of arterial...
 4 Limitations in the...
 5 Future perspectives: search...
 6 Conclusions
 References
 
For a long time the blood vessel has been considered a rigid tube in which plaque increase results in corresponding narrowing of the lumen. It is common knowledge that blood vessels accommodate an increase in blood flow by arterial growth. However, only a decade ago it was described in macaque monkeys that radial enlargement of vessels can also occur in response to progressive plaque growth [1]. These histo-morphometric observations were confirmed in post mortem studies of human coronary arteries [2]. With the clinical application of intravascular ultrasound (IVUS) it became apparent just how ubiquitously remodeling occurs in the presence of the atheroma and how it hides atherosclerotic lesions from angiographic detection [3,4].

Arterial remodeling is now being recognized as an important determinant in most vascular pathology in which narrowing of the lumen is the predominant feature. Not only expansive remodeling, e.g., enlargement, but also constrictive remodeling, e.g., shrinkage, is observed in arterial occlusive disease [5–9]. The mode of remodeling may vary strongly over the length of the artery and constrictive and expansive remodeling may be observed within centimeters of distance (Fig. 1). Expansive remodeling prevents and constrictive remodeling accelerates narrowing of the lumen [5,9]. Also in restenosis after balloon angioplasty, in both experimental research [10–12] as well as in humans [13], constrictive remodeling is the most important determinant of luminal renarrowing.


Figure 1
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  		Fig. 1 Top panel: Cross-sectional area changes along a femoral artery segment obtained at post mortem (patient, male 85 years) and in which lumen area is mainly determined by vessel size. Cross-sections that had been obtained at regular intervals of 0.5 cm and were stained with Lawson's elastin stain. In each cross-section the lumen area, plaque area and vessel area was measured. The arterial segment is represented as if all lesions were completely concentric. The interrupted line represents the internal elastic lamina. The solid line represents the luminal border. The diameter of the schematic lumen represents the cross-sectional area of the lumen. Note that the change in lumen area is mostly accompanied by a change in vessel area but not in plaque area. The latter is depicted in the bottom panels. Bottom panel: The left panel shows the absent relationship between plaque area and lumen area along the femoral artery segment. An inverse relationship would be expected if plaque area increase results in an equal lumen area decrease. The right bottom panel demonstrates the positive relationship between the vessel area (remodeling) and lumen area.

 
The descriptive observations on the existence of the different remodeling modes and their relation with luminal (re)narrowing has changed the perception on the mechanisms of arterial occlusive disease. In the present paper we review the current status of research in the field of arterial remodeling in cardiovascular disease. Mechanisms of arterial remodeling, potential interventions to influence the mode of remodeling as well as the methodological limitations of remodeling studies are discussed.


   2 Arterial remodeling: new perspectives for clinically relevant issues
Top
 Abstract
 1 Introduction
 2 Arterial remodeling: new...
3 Mechanisms of arterial...
 4 Limitations in the...
 5 Future perspectives: search...
 6 Conclusions
 References
 
2.1 Remodeling as a major determinant of luminal narrowing
In de novo atherosclerosis as well as in restenosis two factors are related to the severity of luminal stenosis: plaque mass/intimal hyperplasia and the direction of arterial remodeling [5,6,14]. The relation between plaque mass or intimal hyperplasia increase and lumen area decrease is only moderate [5,14,15]. Understanding of the mechanisms responsible for the different types of arterial wall remodeling might lead to new strategies for the treatment of atherosclerotic luminal narrowing.

2.2 Remodeling and the outcome of balloon angioplasty
In previous studies, we [16] and other investigators [17] hypothesized that local shrinkage in de novo atherosclerosis and restenosis share common pathways. In animal [16] and clinical studies [17] the impact of the type of de novo atherosclerotic remodeling on the long term outcome of balloon angioplasty has been investigated. In the animal study, no relationship was observed between the direction of de novo atherosclerotic and restenotic remodeling. This observation in the atherosclerotic pig does not support the postulation that de novo atherosclerotic and restenotic remodeling are initiated by identical locally determined triggers. A clinical study, however, using serial intravascular ultrasound revealed conflicting results: loss in vessel area was significantly larger for de novo atherosclerotic constrictively remodeled compared with expansively remodeled lesions [17].

There are more consistent results on the impact of de novo atherosclerotic remodeling on the mechanism and the immediate outcome of balloon angioplasty [18,19]. The mode of atherosclerotic remodeling is not related to the luminal gain. However, the mode of arterial remodeling affects the dilatation mechanism: more stretch (increase of vessel size), and less plaque reduction is observed in arterial segments that show constrictive remodeling compared with expansively remodeled segments [18,19].

2.3 Remodeling and plaque vulnerability
The absence of a relation between plaque rupture and angiographic luminal stenosis is often explained as a statistical phenomenon: the lesions with potentially vulnerable plaques and minor luminal narrowing outnumber those that are hemodynamically significantly narrowed [20]. Another explanation for this feature is that expansive remodeling is associated with plaque vulnerability [21]. Indeed, recent observational studies using in vivo intravascular ultrasound [22–24] and post mortem histology [25] revealed that de novo atherosclerotic remodeling has paradoxical effects on the lumen. Expansive remodeling prevents luminal narrowing but hides plaques that are more prone to rupture. On the other hand constrictive remodeling accelerates luminal narrowing but is associated with more stable plaques [25]. More recently, Dangas et al. [26] demonstrated that pre-intervention expansive remodeling is an independent predictor of target lesion revascularization after non-stent intervention. Lesion based revascularization was necessary in 31 and 20% of the expansive and constrictive remodeled lesions, respectively. These results confirm that remodeling in de novo atherosclerosis is a double edged sword: on the one hand expansive remodeling prevents the lumen from being occluded by atherosclerotic plaque formation. On the other hand, however, expansively remodeled lesions may comprise a group of lesions that is highly vulnerable and prone to rupture.


   3 Mechanisms of arterial remodeling
Top
 Abstract
 1 Introduction
 2 Arterial remodeling: new...
 3 Mechanisms of arterial...
4 Limitations in the...
 5 Future perspectives: search...
 6 Conclusions
 References
 
Studies on the mechanisms of arterial remodeling are scarce and hampered by its multifactorial origin since changes in vessel size may be associated with local, regional as well as with individually related factors [6].

3.1 Flow related remodeling
Hemodynamic stimuli like flow and circumferential stress induce arterial remodeling to achieve homeostasis of shear stress and wall tension, respectively [27]. Flow related remodeling depends on the presence of endothelium [28]. After 1 month of altered shear stress, the change in vessel size to maintain a certain shear stress level will become structural by remodeling of the arterial wall [29]. In immature animals, however, the artery may fail to adapt to an increase of shear stress of up to 60%, implying that a shear stress threshold exists for the artery to adapt morphologically [30].

Nitric oxide is found to be an essential intermediate in the shear induced remodeling response. L-NAME, a competitive inhibitor of NO-synthesis impairs the expansive remodeling response if flow is increased [31,32]. In addition, when flow increase occurs, the endogenous NO-synthase knockout mouse lacks a compensatory expansive remodeling response whereas medial hyperplasia is enhanced [33].

Any arterial restructuring requires breakdown of the extracellular matrix which is supported by the non-specific up regulation of the matrix metalloproteinases (MMPs). In both expansive and constrictive flow induced remodeling, activation of MMP-2 and MMP-9 are enhanced and probably regulated at a post-transcriptional level [34,35]. This enhanced MMP-activity proves to be an essential feature in the remodeling response since enlargement of the arterial wall is blocked by MMP-inhibitors [36]. But then the question remains: what regulates the direction of the remodeling response? One clue might be found in the difference in time course of MMP up regulation between the remodeling modes. More rapid increase in MMP expression is observed in flow enhancement compared with flow reduction [35]. Alteration in vessel size in flow enhancement is associated with the rapid production of endothelium derived nitric oxide [31], whereas a longer time is needed before flow reduction accentuates the expression of mitogenic and fibrogenic growth factors [37].

3.2 De novo atherosclerotic remodeling
While the importance of remodeling has been established, further investigation of de novo atherosclerotic remodeling is hampered by methodological problems. Ideally, atherosclerotic remodeling should be studied in humans in a longitudinal study at the same sites at multiple time points [15]. However, the slow and unpredictable progression of atherosclerotic disease makes this impractical and ethically difficult. In addition, animal models in which both directions of remodeling are observed are lacking. Several reports exist on the relationship of risk factors for atherosclerosis and local constrictive remodeling of the culprit lesion but seem conflicting [38–41]. One cross-sectional study in femoral arteries revealed a relationship between the mode of remodeling and plaque structure [25]. Vulnerable lesions were observed more frequently associated with expansive remodeling suggesting that inflammation is an etiologic factor in arterial enlargement. This post mortem observation was supported by clinical studies in which unstable syndromes were associated with expansive remodeling at the culprit lesion site [22–24]. Because of their cross-sectional design, these post mortem and IVUS studies, however, merit careful consideration. Speculations on the mechanisms of de novo atherosclerotic remodeling, therefore originate from serial studies in other arterial remodeling types that can be studied in an experimental setting. In restenosis, intravascular ultrasound measurements of the vessel areas can be compared that are obtained immediately after intervention and at follow up. With providing hemodynamic stimuli, the difference in arterial diameters before intervention and at follow up is measured. Variations in regional shear stress play an important role in the development of the atherosclerotic lesion [42,43]. In the search for the mechanisms in de novo atherosclerotic remodeling a role of hemodynamics has been postulated. The prevailing theory is that when initial plaque growth tends to narrow the lumen, local shear stress increases [2]. The endothelium reacts to the increase in shear stress by increasing NO production and release, with chronic vasodilation as a consequence [44]. Endothelial dysfunction occurs early in the atherosclerotic process [45] resulting in an inadequate reaction to alterations in local shear forces. Thus, mainly eccentric lesions in which part of the wall is non-diseased, would show compensatory enlargement. One post mortem study of human and primate specimen showed results that would support this hypothesis [41]. However, in a recent post mortem study in coronary and femoral arteries, no relationship was observed between the extent of the plaque free vessel wall and the mode and degree of arterial remodeling [46]. These are all descriptive studies, however, and since endothelial dysfunction may occur without evidence of atherosclerotic plaque it is likely that plaque free vessel wall is not a reliable surrogate endpoint for a normal endothelial response to alterations in shear stress [45].

3.3 Remodeling after balloon angioplasty
Constrictive remodeling is a major factor in restenosis after angioplasty and atherectomy in humans [13,47] as suggested earlier in experimental animals [10–12]. Inhibition of constrictive remodeling after balloon angioplasty has been achieved in atherosclerotic and non atherosclerotic animal models [48–52]. The site of action at which remodeling is influenced, however, differs among these experimental studies.

3.3.1 Shear stress
In restenotic arterial remodeling the possibility of a regulating role for shear stress is currently being explored. Recently, Krams et al. [53] locally quantified shear stress in 3D vessel reconstructions after balloon angioplasty in the Yucatan micropig. They reported that the level of decrement in shear stress predicted the loss of vessel area during follow up after balloon angioplasty. This observation is somewhat surprising since by balloon angioplasty the shear registering cell (endothelium) is removed and, after reendothealization, initially dysfunctional [54]. The local shear stress as determined after angioplasty was found to be more predictive than the acute luminal gain. Lumen gain and decrement of shear stress are related. Whether luminal gain is a confounder in the shear stress-remodeling relationship or whether decrement of shear stress is the intermediate in the gain-remodeling relationship needs to be investigated. In support of the role of shear stress in the remodeling response is the observation that low flow up regulates MMP-2 after balloon injury [34].

Expression of most shear sensitive mediators is also stretch responsive and interaction between stretch and shear signal pathways appear to exist [55,56]. In hypertensive remodeling, medial hypertrophy is the most pronounced morphologic feature which is related with increased circumferential stress [57]. The relation of stretch with shear in the processes of arterial remodeling is relatively unexplored.

3.3.2 Oxidative stress
Constrictive remodeling has been prevented successfully by inhibiting oxidative stress [50,58]. In humans, the antioxidant probucol has proven to exert its antirestenotic effects by improving expansive remodeling after angioplasty [58]. In contrast with other serial IVUS studies, however, in this clinical study constrictive remodeling was not a predominant feature in the control group who did not receive probucol. Thus, it could not be concluded that constrictive remodeling was prevented by probucol although it did enhance the expansive remodeling response.

3.3.3 The endothelium
Indirect evidence exists supporting the postulation that dysfunctional endothelium is one plausible initiator of constrictive remodeling. Lafont et al. [59], recently demonstrated that constrictive remodeling was associated with impaired relaxation in response to acetylcholine infusion. It has been postulated that enhanced post angioplasty oxidative stress may contribute to this endothelial dysfunction by enhancing breakdown of NO [59]. The endothelial function is impaired after balloon angioplasty [54] and can be restored by local delivery of the NO precursor L-arginine [60].

Conflicting reports exist on the effect of L-arginine administration on post angioplasty remodeling [49,61]. In the hypercholesterolemic rabbit, Tourneau et al. [61] observed impaired neointima formation in response to L-arginine administration compared with a control group. In the same study by Tourneau et al., administration of L-NAME resulted in almost 80% more intimal hyperplasia compared with animals treated with L-arginine. However, this reduced neointimal formation did not result in a larger lumen since less expansive remodeling was observed in the L-arginine treated group compared with the control group [61]. Swarzacher et al. [60] also observed inhibition of neointima formation after local intramural delivery of L-arginine, but the baseline vessel diameter did not change at two weeks follow up. In contrast, others [49] did observe a beneficial, expansive remodeling effect of L-arginine after balloon angioplasty. In the pig, adenovirus mediated transfer of human endothelial NO-synthase reduced the late lumen loss after balloon angioplasty by both reduction of neointima and enlargement of the vessel area [62].

3.3.4 Collagen turnover
Another target for intervention in experimental restenotic remodeling studies is collagen metabolism. As in flow related remodeling, breakdown and build up of the extracellular matrix is likely to occur during the restenotic remodeling response. The expression of procollagen RNA rapidly increases after balloon injury, whereas collagen content increases after 14 days [63]. The delay between increased expression on RNA level and the actual increase of collagen is likely due to enhanced matrix breakdown within the first weeks after angioplasty. The role of the collagenous adventitia, which determines the stiffness of the artery, in constrictive remodeling is unclear. Balloon angioplasty induces adventitial thickening [64] which is found to be related with the degree of constrictive remodeling [12]. However, formation of the neoadventitia is one of the earliest morphological features observed within 3 days after balloon angioplasty [65] while constrictive remodeling begins only after 1 week [66]. The latter is consistent with serial IVUS studies in humans in which the vessel area decreases between 1 and 6 months [67]. In addition, in rabbit arteries collagen content is significantly lower in restenotic versus non-restenotic vessels after balloon angioplasty [68] which is difficult to reconcile with a presumed increased adventitial collagen content in constrictive remodeling [12]. Thus, controversial reports exist on the relation between adventitial thickness, collagen content and the mode of arterial remodeling after balloon angioplasty. Probably not the deposit of total collagen but the maturation with subsequent conformational changes and cross-linking of collagen are an important determinant of geometrical changes within the arterial wall [69].

Balloon angioplasty, in combination with low blood flow, up-regulates MMPs on RNA-level [34]. Recently, we studied the effect of the MMP-inhibitors Batimastat and Marimastat on late lumen loss after balloon angioplasty in the pig. In the atherosclerotic pig, Batimastat reduced late lumen loss by 50% which was completely attributed to impaired constrictive remodeling [51]. In the non atherosclerotic pig, Marimastat completely abolished constrictive remodeling resulting in reduction of late lumen loss of more than 50% [70]. These experimental studies show that breakdown of the extracellular matrix is a prerequisite for an artery to remodel in response to balloon angioplasty. One has to keep in mind, however, that proteases are also obligatory for the maturation of procollagen: propeptides are cleaved by Bone Morphogenetic Protein 1 (BMP) and furin [71]. Since non specific MMP-inhibitors are tested, it should be studied whether the effect of MMP-inhibition in experimental studies is attributed to the suppression of matrix breakdown, collagen maturation or both.

3.3.5 Growth factors
While the role of growth factors has extensively been studied in relation to neointima formation [72,73], their role in arterial remodeling is relatively unexplored. Inhibition of growth factors like platelet derived growth factor (PDGF) may not only influence neointima formation but also the constrictive remodeling response. Tyrosine kinases are transducers of a variety of extracellular signals that regulate smooth muscle cell proliferation and differentiation. Receptors for several growth factors like PDGF and fibroblast growth factor-2 have tyrosine activities. In animals, Tyrosine kinase inhibitor experimentally suppresses restenotic changes of the coronary artery after balloon injury in pigs [48] by inhibiting intimal hyperplasia as well as constrictive remodeling.

Transforming growth factor-β (TGF-β) is suggested to play a role in expansive remodeling after balloon angioplasty [74,75]. A function blocking antibody to the {alpha}vβ3 receptor, resulted in enhanced constrictive remodeling after arterial injury. This effect of the {alpha}vβ3 receptor blockade may be due to a decrease of TGF-β accumulation [74]. This postulation, however, is in contrast with the results of the study by Smith et al. [75] who injected recombinant soluble TGF-β type II receptor in injured rat carotid arteries. Treatment with TGF-βRII results in inhibition of biological responses mediated by several isoforms of TGF-β. TGF-βRII treatment resulted in a reduction of late lumen loss of 88% that could mainly be attributed to a reduction of constrictive remodeling. This reduction of constrictive remodeling was associated with an impaired induction of smooth muscle alfa actin expression and mRNA collagen type I and III levels [75].

3.3.6 β and {gamma} irradiation
Ionizing radiation has been shown to reduce vascular lesion formation after balloon injury and stenting [76]. In the pig coronary artery, irradiation also resulted in a larger vessel perimeter at follow up compared with non-irradiated vessels [77]. Thus, brachytherapy might have a beneficial effect on both intimal hyperplasia and on constrictive remodeling after balloon angioplasty. Irradiation resulted in impaired adventitial cellular proliferation early after treatment [76]. Two weeks after angioplasty fewer {alpha}-actin positive myofibroblasts are observed compared with nonirradiated controls suggesting that irradiation inhibits adventitial collagen deposition and fibrosis and subsequent constriction [76–78]. Another postulated mechanism by which irradiation might influence arterial remodeling is by enhancing the number of apoptotic cells and the subsequent impairment of macrophage population [79]. However, although macrophages invade the arterial wall after injury, their causal role in the direction of arterial remodeling is still unclear. In addition, an increase of apoptotic cells as estimated by TUNEL labeling was not observed after arterial irradiation by Waksman et al. [77].


   4 Limitations in the study of arterial remodeling
Top
 Abstract
 1 Introduction
 2 Arterial remodeling: new...
 3 Mechanisms of arterial...
 4 Limitations in the...
5 Future perspectives: search...
 6 Conclusions
 References
 
4.1 Visualization of local variation of the remodeling response
If, upon a trigger, remodeling would occur equally throughout the arterial system, then random sampling would suffice to study this process. Unfortunately, local arterial remodeling is a common phenomenon that varies strongly over the length of the human artery [5] and also in the atherosclerotic Yucatan micropig model [16]. This makes local visualization of the remodeling response a necessity. Studying the local in vivo remodeling response with examinations on a tissue level requires careful local matching of the site of interest and reference site with the use of intravascular ultrasound, angiography and histology.

4.2 The reference
In post mortem and single ultrasound observations, only a single static visualization on a dynamic process is obtained. Culprit of non-serial studies on arterial remodeling is the choice of the reference site. The artery may be generally affected by the atherosclerotic disease which hampers the identification of a proper reference that contains the least amount of plaque. In addition, tapering also influences arterial size, and correction for tapering may be difficult if numerous side branches are present. In the case of single IVUS studies and post mortem observations it would be most appropriate not to consider the vessel in terms of expansive or constrictive remodeling but rather in terms of variations in vessel size along the arterial segment.

Although de novo atherosclerotic lesions develop over decades, the first short term serial IVUS study on the influence of arterial remodeling on luminal narrowing has recently been published. Shiran et al. [15] showed that decrease in lumen area was related with decrease in vessel size but not with increase in plaque size.

The aforementioned limitation of studies on de novo atherosclerotic remodeling does not account for examinations of arterial remodeling in restenosis. Remodeling in restenosis is a process which occurs within months which makes it easier to study over time using intravascular ultrasound [13].

4.3 Extrapolation of animal models to the human atherosclerotic artery
Due to the aforementioned reasons it is difficult to study de novo atherosclerotic remodeling over time. In some animal models, atherosclerotic lesions develop much more rapidly and plaque morphology closely resembles that observed in humans [80]. Remodeling patterns, however, differ substantially. Expansive remodeling is observed and first described in animals [1], but a model in which local de novo atherosclerotic constrictive remodeling occurs is lacking. Another feature that seems unique for the human situation is rupture of the atherosclerotic plaque that is also not under study in animals.

Constrictive and expansive remodeling after balloon angioplasty have extensively been reported in different animal models. In remodeling in restenosis, however, the time frame over which constrictive remodeling develops seems to differ between animals and humans. In the atherosclerotic pig constrictive remodeling gradually develops within a week after balloon angioplasty and seems maximal at 6 weeks [10,16]. In humans, the artery shows expansive remodeling in the first month while constrictive remodeling is recognized between 1 and 6 months after intervention [67].

A major part of the aforementioned animal experimental research has been performed in peripheral vessels. The response to injury inflicted by balloon dilation may differ between the coronary and peripheral arteries [81]. These differences should be considered extrapolating results obtained in animal to the atherosclerotic human coronary artery.


   5 Future perspectives: search for the best target to influence remodeling
Top
 Abstract
 1 Introduction
 2 Arterial remodeling: new...
 3 Mechanisms of arterial...
 4 Limitations in the...
 5 Future perspectives: search...
6 Conclusions
 References
 
In order to modify arterial remodeling, specific targets to intervene in this process need to be identified. To select an appropriate target, fundamental knowledge of mRNAs and proteins involved in the process is a necessity, to detect which proteins are involved (mRNA analysis) and if their expression is changed (protein analysis). In the different types of arterial remodeling, like flow induced, de novo and restenotic remodeling, the vascular extracellular matrix which forms the arterial skeleton has to change [51,63]. However, how this skeleton restructuring is initiated and controlled in the different types of remodeling or how its mode is determined is still unknown. As mentioned earlier, the role of hemodynamics is postulated in flow-induced [12,28,29], de novo atherosclerotic and restenotic arterial remodeling [54]. The described involvement of the endothelial cell layer and the extracellular matrix in arterial remodeling makes them appropriate targets for intervention.

5.1 The endothelial cell as a target for intervention
In response to shear and tensile stresses, endothelial cells produce a range of vasoactive substances and growth factors like PDGF, TGF-β, FGF-2, NO, angiotensin II and endothelin-1 which have an effect on collagen turn-over [75,82–84]. Each substance is a potential candidate to influence initiation and progression of the remodeling process. It is likely, however, that remodeling can be initiated by more than one factor. Interestingly, different growth factors including PDGF-B have a shear stress responsive element [85]. Although intracellular, this might be an appropriate target to prevent initiation of remodeling. Acceleration of re-endothelization by VEGF might be another way to prevent constrictive remodeling. Local delivery of rhVEGF reduced in-stent intimal formation [86] but might also be beneficial to prevent constrictive remodeling.

5.2 The matrix as a target for intervention
Changes in arterial wall structure occurs in all types and modes of arterial remodeling. In restenotic [16] and flow-induced remodeling [28] structural matrix changes occur late in the remodeling process. It is likely that the vascular wall uses common pathways to initiate and maintain the different types of remodeling although mechanical triggers may differ. Evidence for this is found in collagen breakdown studies. It is reported that in de novo atherosclerotic remodeling, in post angioplasty remodeling as well as in flow related remodeling matrix metalloproteinases play an important role [34,51]. MMP inhibition studies support this postulation [36,51]. Next to collagen breakdown, synthesis and maturation of collagen are also appropriate targets to intervene in the arterial remodeling process. Synthesis can be affected by using an inhibitor of collagen synthesis [87] but also the maturation process of collagen might be an appropriate target by, for instance, interfering in collagen cross-linking [69]. Other potential sites of application are BMP-1 and a furin-like proprotein convertase that are responsible for the N- and C-terminal cleavage of collagen-1 during maturation [88].

Another component of the vascular matrix are the elastins. The elastases, cathepsin S and K are not present in normal arteries but are present in macrophages and smooth muscle cells localized in human atheroma which supports a role for elastolytic cathepsins in vessel wall remodeling [89] and suggests a possibility to intervene, via this elastases, in elastin turn-over.

5.3 Identification of mRNAs involved in arterial remodeling
In atherosclerotic arteries processes like plaque accumulation, inflammation, proliferation (neointima formation) and remodeling occur simultaneously which makes it hard to determine which mRNAs are specifically involved in remodeling.

Balloon dilation of arteries in an animal model makes it possible to study the remodeling process at different time points but also here remodeling occurs next to other processes that confound mechanistic studies like inflammation and proliferation. During arterial remodeling following a change in blood flow, no inflammation, neointima formation or plaque formation occurs which makes this a relative ‘clean’ model to detect mRNAs specifically involved in arterial remodeling. Moreover, the mode of remodeling will be expansive after flow increase or constrictive after flow decrease [28,29,33,35]. In this flow related and endothelium dependent model, however, it is unknown to what extent results can be extrapolated to other types of remodeling that occur in response to injury. In this controlled experimental environment, several open approaches like differential screening [90], differential display [91] and subtraction PCR [92], are available to identify new mRNAs involved in initiation, control and determination of the mode of the structural change. Next to this, the search facilities for the rapidly growing databases for human and animals are much improved which makes the identification of mRNAs relatively easy.


   6 Conclusions
Top
 Abstract
 1 Introduction
 2 Arterial remodeling: new...
 3 Mechanisms of arterial...
 4 Limitations in the...
 5 Future perspectives: search...
 6 Conclusions
References
 
Arterial remodeling is a major determinant of obstructive cardiovascular disease. Compared to plaque/neointima formation, the mechanisms of the different remodeling modes have been relatively unexplored. This is mainly due to the lack of animal models in which expansive as well as constrictive remodeling are observed. Recently, several investigators have reported successful blocking of the constrictive remodeling response after balloon dilation and expansive response after flow enhancement in animal experimental models. With rapidly accumulating knowledge of the mechanisms of arterial remodeling, potential targets for intervention are being identified that have great potential for future therapeutic strategies in the treatment of obstructive arterial disease.

Time for primary review 26 days.


   References
Top
 Abstract
 1 Introduction
 2 Arterial remodeling: new...
 3 Mechanisms of arterial...
 4 Limitations in the...
 5 Future perspectives: search...
 6 Conclusions
 References
 

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