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Cardiovascular Research 1998 38(1):54-68; doi:10.1016/S0008-6363(97)00326-X
© 1998 by European Society of Cardiology
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Copyright © 1998, European Society of Cardiology

Endothelial regrowth after arterial injury: from vascular repair to therapeutics

Eric Van Bellea, Christophe Bautersa,*, Takayaki Asaharab and Jeffrey M. Isnerb

aDepartment of Cardiology, University of Lille, Lille, France
bDepartment of Cardiovascular Research, St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA

* Corresponding author. Service de Cardiologie B, Hôpital Cardiologique, Boulevard du Professeur J. Leclercq, 59037 Lille Cedex, France. Tel. (+33-3) 2044 5302; Fax (+33-3) 2053 5874; E-mail: cbauters@chru-lille.fr

Received 26 September 1997; accepted 9 December 1997

Interventional strategies for patients with coronary artery disease such as percutaneous transluminal coronary angioplasty or coronary stent implantation invariably result in a marked degree of vascular injury (deendothelialization, mechanical damage to the medial and adventitial layers) [1–3].

The loss of the endothelial monolayer is associated with a variety of deleterious consequences such as thrombus formation, neointimal thickening, and abnormal responses to endothelium-dependent agonists [3–5]. These effects may contribute to each of the known limitations of these techniques (vessel occlusion, restenosis, coronary spasm).

The objective of the present review will be to present applied reendothelialization as a possible treatment for patients with coronary artery disease undergoing mechanical revascularization. Our aim will be twofold: first, to summarize current knowledge on the beneficial effect of endothelial regrowth after arterial injury; second, to discuss the potential role of growth factors or other compounds to accelerate reendothelialization.


   1 The ‘normal’ endothelial layer
Top
 1 The 'normal' endothelial...
2 Spontaneous endothelialization...
 3 Applied reendothelialization...
 4 Beside growth factors
 5 Future prospects
 References
 
Occupying a strategically important location between circulating blood and tissues and having the ability to respond to changes in its physical, chemical, and humoral environment by the production of bioactive substances, the normal endothelium controls the tone and the proliferative state of the underlying vascular smooth muscle cells (VSMCs) and maintains a non-adhesive luminal surface. Modulation of VSMC tone is mediated by the synthesis and release of endothelium-derived relaxing and contracting factors. The proliferative state of VSMCs is controlled through these endothelium-derived factors and through the secretion of matrix proteins. Anticoagulant, fibrinolytic, and antithrombotic properties of the endothelium contribute to the maintenance of the fluidity of the blood.

1.1 Endothelium-dependent vasomotion
1.1.1 Relaxing factors
Prostacyclin (PGI2), a potent vasorelaxant and platelet-inhibitory metabolite of arachidonic acid was the first endothelium-derived vasoactive factor discovered [6]. After the seminal observation of Furchgott and Zawadski in 1980 [7]that an intact endothelial layer was required for acetylcholine-induced vasorelaxation, further studies demonstrated that a labile, diffusible, nonprostanoid substance called endothelium-derived relaxing factor (EDRF) mediates endothelium-dependent vasorelaxation [8]. Based on the striking similarities between nitric oxide (NO) and EDRF it was postulated that EDRF and NO were identical [9]. Measurement of NO production by endothelial cells provided direct evidence for this hypothesis [10].

The endothelial cell (EC) synthesizes EDRF-NO from the terminal guanido nitrogen atom(s) of L-arginine [11]. The enzyme (NO-synthase) responsible for this reaction has been isolated and characterized [12]. Several isoforms of NO-synthase were identified: two isoforms, present in endothelial (eNOS) and neuronal cells (nNOS), which require calcium and calmodulin, and a form (iNOS) which is Ca2+-independent and can be observed in immunoactivated cells, including ECs and VSMCs, after treatment with endotoxin, tumor necrosis factor (TNF) or other cytokines [13]. The arginine-NO signaling pathway appears thus to be ubiquitous, and may contribute to a variety of biological functions [13].

In addition to EDRF-NO, the existence of other nonprostanoid relaxing mediators [14], including an endothelium-derived hyperpolarizing factor (EDHF) [15], has been proposed. It has been postulated that EDHF may be an endogenous activator of potassium channels in VSMCs [15].

1.1.2 Contracting factors
The endothelium-derived contracting factors mediating endothelium-dependent vasoconstriction belong to two categories: (a) vasoconstrictor metabolites of arachidonic acid (TXA2, endoperoxides) and (b) a potent peptidergic vasoconstrictor substance named endothelin-1 [16–18]. Endothelin-1 acts on vascular smooth muscle through endothelin-A receptors and is the most potent endogenous vasoconstrictor yet identified. Endothelin-1 is not stored in endothelial cell but m-RNA expression, protein synthesis and secretion are induced within minutes by appropriate stimuli such as angiotensin II, catecholamines, growth factors (basic FGF) or thrombin [18]. The production of endothelin-1 is inhibited by nitric oxide and prostacyclin [19, 20]. In addition, angiotensin II (Ang II) may also be regarded as an endothelium-derived contracting factor: angiotensin converting enzyme (ACE) has been localized in the ECs of capillaries and large arteries and vein throughout the vasculature [21], while bovine aortic cells in culture express renin and are able to synthesize Ang II intracellularly [22, 23].

In addition, the production of superoxide anion, elicited in ECs through an NADH-dependent pathway [24], may also be considered, by its effects on EDRF-NO, as a contracting agent. Indeed EDRF is rapidly inactivated by superoxides [25, 26]while superoxide dismutase reverses this effect [27, 28].

1.2 Growth inhibitory effect on underlying vascular VSMCs
The endothelium produces a number of molecules that stimulate VSMC proliferation (e.g., endothelin, platelet derived growth factor,...) [29, 30]and is also responsible for the modulation of compounds such as angiotensin that have been implicated in growth-related metabolism [31, 32]. Because VSMCs in the mature, healthy blood vessel wall exhibit minimal proliferation activity [33, 34], the actions of these growth promoters must be countered by factors that inhibit such metabolism. The endothelium is the likely source of such molecules because, when damaged, VSMC proliferation is an almost immediate response [35, 36]. This observation suggests that the intact endothelium produces both growth promoters and inhibitors in a balanced, coordinate manner. It has been shown for some time that ECs are a source of heparin and heparin sulfates, which do have growth-inhibitory properties. More recently, it has also been suggested that EDRF-NO also acts as a powerful growth modulator.

1.2.1 Heparin/heparan sulfate proteoglycans
Growth inhibition of VSMCs, when in coculture with ECs, was primarily ascribed to the actions of endothelium-derived heparin/heparan sulfate proteoglycans [37–39]. Addition of heparin or heparan sulfate glycosaminoglycans to tissue culture medium inhibits VSMC growth [38–40]. Infusion of heparin reduces neointimal proliferation in balloon abraded arteries [41]. In vitro and in vivo studies suggest that heparin may prevent VSMC entry into the S phase of the cell cycle [42, 43].

1.2.2 EDRF-NO
The intracellular increase in cyclic GMP, a part of the signal transduction of EDRF-NO, and NO donors depress the incorporation of 3H-thymidine in DNA in cultured VSMCs [44]. The physiologic relevance of this effect was corroborated by results of co-culture experiments in which the inhibitory effect of ECs on VSMC growth was increased when cultured cells were incubated with L-arginine, the substrate for EDRF-NO synthesis, while this effect was decreased when cells were incubated with nitro-L-arginine, a L-arginine analog blocking the NO synthase [45]. These observations were confirmed by studies performed in vivo in models of balloon injury [46, 47]and of atherosclerosis [48, 49]. In these studies, L-arginine inhibited neointimal formation and this effect was reversed by L-NAME (N-nitro-L-arginine-methyl-ester), an other L-arginine analog blocking NO synthase.

1.3 Endothelium as an antithrombotic layer
The normal properties of the endothelium include the maintenance of a non-adhesive luminal surface and anticoagulant, fibrinolytic, and antithrombotic actions. The maintenance of normal blood fluidity and the preservation of a non-thrombogenic surface is characterized by several EC membrane regulatory mechanisms.

ECs synthesize heparin-like glycosaminoglycans that bind antithrombin III and catalyze the inactivation of coagulation proteases such as thrombin and factor X [50], providing potent antithrombin activity of the vascular surface and protecting against thrombus formation. They also constitutively synthesize thrombomodulin, an intrinsic membrane receptor that binds thrombin, and converts it into a potent activator of protein C. Activated protein C acts as an anticoagulant in the presence of protein S, inactivating factors Va and VIIa [51], and as stimulus for local fibrinolysis by binding endothelial plasminogen activator inhibitor (PAI).

Intravascular fibrinolysis is initiated at the vessel surface by the synthesis and release by ECs of tissue plasminogen activator (t-PA), a highly specific serine protease that cleaves plasminogen and converts it into plasmin [52]. Additional regulatory control by endothelial synthesis and release of plasminogen activator inhibitor-1 (PAI-1) clearly plays an important role in determining the overall rate and extent of the fibrinolytic process [53].

Endothelial cell-derived PGI2 inhibits platelet activation [6]while EDRF-NO inhibits platelet adhesion and aggregation [54]. Although they have different mechanisms of action, EDRF (NO) and PGI2 can interact synergistically to inhibit platelet aggregation [55].


   2 Spontaneous endothelialization after arterial injury
Top
 1 The 'normal' endothelial...
 2 Spontaneous endothelialization...
3 Applied reendothelialization...
 4 Beside growth factors
 5 Future prospects
 References
 
2.1 The vascular response after arterial injury
Balloon arterial injury is associated with EC loss exposing the underlying vessel wall which is immediately covered by a layer of platelets and leukocytes [29, 56, 57]. Platelets contain chemotactic factors and mitogens for VSMCs, such as PDGF, which are released in the injured vessel wall [57]. After balloon injury, reendothelialization of the injured vessel proceeds from areas of intact endothelium to reconstitute the endothelial lining.

Balloon injury also induces stretching and lysis of some of the cells, mainly VSMCs, of the underlying layers; this leads to the activation of VSMCs. This activation is associated with a shift from a contractile to a synthetic phenotype [29, 58]and leads to VSMC proliferation and migration and synthesis of extra-cellular matrix which are responsible for intimal thickening [3, 59]. Neointimal hyperplasia has also been documented in humans: histological studies have shown that intimal thickening in the restenotic lesion contains VSMCs in an abundant extracellular matrix [3, 57].

It was recently shown, both in atherosclerotic models and in humans, that in addition to the two above phenomenon the response to balloon injury is associated with a change in the external size of the artery at the injured site, a process termed ‘vascular remodeling’ [60–63]. At least two components of vessel remodeling after balloon angioplasty have been described: (1) constrictive remodeling which is deleterious in term of lumen size and may be the consequence of vessel constriction due to a retractile scar; and (2) adaptive enlargement which is beneficial in term of lumen size and tends to compensate for neointimal formation. In the atherosclerotic rabbit model, Kakuta et al. and Lafont et al. demonstrated that vascular remodeling was the main determinant in lumen size at follow-up (i.e., restenosis) [61, 62]. Similarly, vessel remodeling has been confirmed as a major determinant of restenosis after balloon angioplasty in humans [63]. The biological determinants of this process are unknown.

2.2 The natural history of endothelial regrowth after arterial injury
In the hours following experimental angioplasty, ECs rapidly enter the replication cycle to restore endothelial continuity. Proliferation and migration can be initiated either by loss of contact inhibition, stretch or growth factors secreted by ECs, VSMCs and circulating cells [64, 65]. Endothelial regeneration starts from the leading edge of the denuded area and from the ostia of collateral arteries [66]. This process begins within the first 24 hours after arterial denudation and ceases 6 or 10 weeks later, depending upon animal species [67]. The rate of endothelial regrowth from the leading edges is related to animal models and experimental conditions; for example in the common carotid artery, the endothelial outgrowth is 8–10 mm in the rat and 5–6 mm in the rabbit [67]. However, the most important factors determining the final reendothelialized area seems to be the extent of the initial deendothelialization and the number of side branches within the denuded area. Indeed, while complete reendothelialization can be achieved after minor degrees of denudation [68, 69]or in vessels with numerous side branches [70, 71], ECs have been found to be incapable of sustained regrowth after widespread denudation [67, 72]. Even if complete reendothelialization occurs, the regenerated endothelium shows abnormal morphologic characteristics. In contrast to normal ECs, regenerating ECs grow as a sheet with close cell-to-cell contacts, no longer aligned with blood flow and are polygonal-shaped and irregular-sized with cytoplasm bulging toward the lumen [66, 67, 69, 70, 73].

In humans, there is limited information on reendothelialization following percutaneous transluminal coronary angioplasty (PTCA) [1, 2]. As in animal models, findings in specimens retrieved early after PTCA demonstrate that balloon injury is associated with a complete loss of the EC lining. In addition, examination of specimens retrieved at later time-points suggests that there is limited reendothelialization at the injured site within 1 month of balloon angioplasty while extensive reendothelialization occurs between 1 and 5 months. Reendothelialization is typically completed 5 months after PTCA.

The factors controlling the response of ECs after balloon injury have not been completely elucidated. It is likely that the release of growth factors for ECs plays a significant role in spontaneous reendothelialization. In the vessel wall, Fibroblast Growth Factor (FGF) — a growth factor for both ECs and VSMCs — is synthesized and stored by ECs and VSMCs [74–77]. Balloon injury induces both a release of stored FGF from injured cells [78, 79], and an increased expression of FGF mRNA from ECs and VSMCs [80]. The effect of FGF on target cells is probably prolonged by the storage of acutely released FGF in the extracellular matrix [81]and amplified by the increased expression of FGF receptors in ECs following balloon injury [80]. The physiological role of endogenous FGF in endothelial repair after arterial injury is emphasized by the co-localization of FGF mRNA and protein with proliferative ECs at the leading edge of reendothelialization [68, 80]. The observation that blood levels of FGF increase after balloon angioplasty in humans suggests that this factor might also be operative in humans [82].

Vascular Endothelial Growth Factor (VEGF) is a more recently described growth factor for ECs [83]. It is synthesized in the vessel wall by VSMCs and its high affinity binding sites are restricted to ECs [83, 84]. The latter observation accounts for the observation that VEGF has no trophic effects on VSMCs. A physiological role for VEGF in endothelial repair has also been suggested by the expression of VEGF mRNA in the vessel wall following balloon injury in rats [85]and by the release of the protein after balloon angioplasty in humans [82].

2.3 Interaction between endothelial regrowth and the other components of the response to injury
2.3.1 Thrombogenicity
As described above, balloon injury is associated with EC loss exposing the underlying vessel wall which is immediately covered by a layer of platelets and leukocytes [29, 56, 57]. This may lead to mural thrombus formation, especially when there is deep vessel wall injury. In the pig model, mural thrombus was observed in 70% and 50% of the specimens retrieved within 1 hour and 24 hours, respectively, after oversized balloon injury of the carotid artery [56, 86]. In this model, mural platelet and thrombus deposition progressively decreased when the endothelial lining reformed. Such thrombi may lead to vessel occlusion [86]and play a role in the formation of neointimal thickening [4]. Indeed in a rat model of balloon denudation, the administration of antibodies directed against platelets was associated with a significant decrease in neointimal thickening [87]. In addition, thrombin itself has potent effects on the growth of VSMCs [88]and antithrombin drugs inhibit experimental restenosis [89]. Finally, the volume of thrombus at the injured site by forming a matrix for subsequent intimal growth may determine the volume of neointima [4].

2.3.2 Neointimal hyperplasia
The key role of the endothelium in controlling the underlying intimal growth has been highlighted by the results of numerous experiments using various models of endothelial injury [35, 70, 71, 90]. The loss of the endothelial lining alone in a large area, with no or minimal medial injury, as performed by a gentle stream of air or a filament loop, is sufficient to induce the formation of a thick neointima within 14 days [35, 68]. The role of spontaneous reendothelialization in limiting this process was suggested by additional experiments. Indeed, endothelial injury on a small defined surface, 3 to 5 cells wide, is associated with complete endothelial regrowth within 8 hours and no intimal formation [91]. In addition, in models with a greater extent of denudation, the areas that reendothelialize first have a lesser degree of intimal thickening [35, 70, 71]while the rate of proliferation rate of VSMCs in the intima is lower in reendothelialized than in non-reendothelialized areas [59]. The mechanisms of this effect involve some of the above described properties of the endothelium such as the restitution of a non-permeable barrier [92, 93]protecting VSMCs against circulating or platelet released growth-promoting factors and the release of growth inhibitory molecules (heparan-sulfates, EDRF-NO). We have to point out, however, that the endothelium, although important, is certainly not the only determinant of the final degree of intimal thickening. Indeed, deep injury to the media with limited EC loss and reendothelialization within few days may also induce intimal thickening [94]while in largely denuded arteries intimal growth may stop before the injured area is completely reendothelialized [71].

2.3.3 Vascular remodeling
Although there is to date no data to definitely demonstrate that the endothelium is involved in vascular remodeling after balloon injury, its potential role has been discussed [95]. As stated above, vascular remodeling after balloon injury is an adaptive process that may or may not accommodate intimal growth. Although all types of vascular cells may participate in the vascular remodeling process, the endothelium is particularly suited to play a prominent part [95]. Indeed the endothelium is strategically located to serve as a sensory cell assessing hemodynamic and humoral signals, as well as an effector for eliciting biologic responses (e.g. EDRF-NO). In this regard the demonstration by Langille and O'Donnel that a structural reduction in vessel size induced by a long-term decrease in blood flow is dependent on an intact endothelium [96]and the recent report that, in a rabbit model of arteriovenous fistula, NO play a role in the adaptive enlargement of the vessel in response to increased blood flow [97]are consistent with this hypothesis.

2.3.4 Neoendothelial function
As described above, ECs tend to restore endothelial continuity after arterial injury. It has been shown, however, that the function of the neoendothelium remains abnormal for weeks after the reendothelialization process has been completed [69, 98, 99]. These studies reported that vessel relaxation elicited through endothelium agonists remained impaired despite endothelial regrowth. In some of these experiments receptor mediated relaxation was specifically altered [98, 99]while in others both receptor- and non-receptor-mediated relaxations were impaired [69]. Possible reasons for this disparity include differences in animal species, arterial beds or the severity of balloon injury. In man an enhanced constrictor response of arterial segments previously subjected to angioplasty has also been documented [5, 100], a finding that is consistent with functional abnormalities of the neoendothelium.

After balloon injury, alteration of neoendothelial properties leads to a reduced production of PGI2 and EDRF-NO [69, 98, 99, 101]while the sensitivity of VSMCs to relaxing (PGI2, EDRF-NO) or contracting factors is unchanged [69, 98, 99]. This finding suggests that the presence of dysfunctional endothelium may favor the occurrence of arterial spasm at sites of angioplasty. Similarly, as PGI2 and EDRF-NO act synergistically to inhibit platelet aggregation and leukocyte adhesion [55, 102], their reduced production could favor thrombus formation. Finally, the reduced production of EDRF-NO, a potent inhibitor of VSMC growth, in regenerated endothelium could play role in neointimal formation. The observation that there is a positive relationship between the severity of endothelial dysfunction and the degree of intimal hyperplasia is consistent with this hypothesis [69]. Overall, these findings indicate that the regenerated endothelium after balloon angioplasty may be dysfunctional with respect to its inhibitory effects on vascular tone, thrombus formation and intimal growth.


   3 Applied reendothelialization using endothelial growth factors
Top
 1 The 'normal' endothelial...
 2 Spontaneous endothelialization...
 3 Applied reendothelialization...
4 Beside growth factors
 5 Future prospects
 References
 
As outlined above, the absence or the abnormal function of the endothelium after arterial injury may lead to a variety of deleterious consequences such as thrombosis, increased neointimal thickening, or lack of vasorelaxation in response to endothelium-dependent agonists. As a consequence, a treatment strategy that would favor the recovery of a functional endothelial layer — i.e., applied reendothelialization — is likely to be associated with beneficial effects at the injury site.

Among the possible strategies tested to increase endothelial regrowth in vivo after arterial injury, the administration of EC growth factors has been the most extensively studied. FGF and VEGF are important growth factors for ECs in vitro [65, 83, 103–105]. While VEGF is specific for ECs, FGFs are also growth factors for other cell types such as, for example, VSMCs [79]. The in vivo administration of these growth factors has been associated with an increased development of collateral vessels in ischemic tissues [106–110]. Both FGF and VEGF have been used in vivo in an attempt to increase endothelial regrowth after experimental arterial injury.

3.1 Reendothelialization after balloon injury
3.1.1 FGF
The first study demonstrating that the in vivo administration of bFGF was associated with a significant increase in EC coverage on denuded arteries was performed by Lindner et al. [65]. In this study, the authors established clear evidence for the mitogenic effect of bFGF on EC replication in vivo, and further demonstrated that total EC regrowth could be achieved within 10 weeks in a rat carotid model of balloon denudation by systemic administration of bFGF. Interestingly, the same dose (120 µg) of bFGF had markedly different responses on the endothelium of previously injured and of uninjured arteries: the increase in the replication index was 30 fold higher in ECs from injured arteries than in ECs from uninjured arteries. As suggested by the authors, the higher sensitivity of ECs of denuded arteries to bFGF may be explained by a higher number of available bFGF receptors when cell density is low [111]. It is of interest to note that recombinant bFGF may achieve significant reendothelialization of denuded arteries when given at much lower doses than in this initial study. In a rabbit model of balloon denudation of the iliac artery, we have observed a significant increase in endothelial regrowth after administration of 2.5 µg of bFGF twice a week for 2 weeks [112]. Finally, the beneficial effect of FGF on endothelial regrowth is not limited to bFGF; administration of low doses of acidic FGF (aFGF) also promotes repair of damaged vascular endothelium in vivo [113].

Although these studies clearly established the beneficial effect of FGF on EC growth in vivo, it was of critical importance to assess the function of the neoendothelium that regenerated in response to the administration of the growth factor. Meurice et al. recently reported the effect of chronic administration of bFGF on physiological responses to endothelium-dependent agonists after vascular injury [112]. In this study, as stated above, administration of relatively low doses of bFGF was associated with a greater degree of reendothelialization. Four weeks after denudation, endothelium-independent responses did not differ significantly between the bFGF and the control groups. In contrast, the maximal endothelium-dependent acetylcholine-induced relaxation of the bFGF-treated animals was significantly greater than that of the control group (Fig. 1). The mechanisms by which bFGF restored the relaxation to acetylcholine are not completely understood but the normalized endothelium-dependent responses observed after bFGF treatment are probably not solely related to endothelial regrowth. As stated above, previous studies performed in rabbit iliac arteries have demonstrated persistent abnormal endothelium-dependent responses even in the case of complete reendothelialization [69]; this suggests that bFGF, in addition to its effect on EC growth, might also modulate some qualitative aspects of ECs and restore normal physiological responses to endothelium-dependent agonists. In favor of this latter hypothesis are the results of a recent study reporting a beneficial effect of chronic administration of bFGF on the functional responses of atherosclerotic vessels in the hypercholesterolemic rabbit [114]. In this model, abnormal endothelium-dependent responses have been documented even in the absence of important structural changes at the endothelial level [115–117]; these abnormal responses are thought to be related to either a reduced synthesis or an enhanced destruction of EDRF [48, 118–120]. The improvement in endothelium-dependent responses in this model again suggests that bFGF, in addition to an anatomic effect on ECs, may also lead to functional changes at the endothelial level.


Figure 1
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  		Fig. 1 Effects of four intravenous bolus of basic FGF, administered from day 1 to day 10 after balloon injury, on endothelium-dependent relaxation at 4 weeks. The persistent impaired response to acetylcholine observed in denuded arteries of placebo-treated animals (denuded placebo) was significantly improved by treatment with basic FGF (denuded bFGF). In addition, the response to acetylcholine in basic FGF-treated animals was close to the response observed in non-injured arteries (non-denuded placebo). (Adapted from Meurice et al. [112]with the permission of the authors.)

 
The effect of FGF administration on neointimal thickening after arterial injury is unclear. Lindner et al. [121], using high doses of bFGF (12 µg/day for 2 weeks in a rat model), found a significant increase in neointimal thickening. By contrast, Bjornsson et al. [113], using low doses of aFGF — a mitogen for VSMCs in vitro [122]— in the same model observed an inhibition of neointimal thickening. Recently, Lazarous et al. gave systemic bFGF to dogs after femoral artery balloon denudation, and there was no increase in intimal thickening [110]. Finally, in the study by Meurice et al. [112], a similar degree of neointimal thickening was observed in control and treated rabbits 4 weeks after injury. Taken together, these studies suggest that the final effect of FGF on neointimal thickening may be the consequence of a balance between stimulatory and inhibitory mechanisms on VSMC growth. As previously discussed, experimental studies support the notion that certain functions of the endothelium such as production of NO are critical to the prevention of luminal narrowing by neointimal thickening [46, 47]. Accelerated reendothelialization may thus reduce neointimal formation. On the other hand, bFGF which is a potent growth factor for VSMCs [79, 121]may directly enhance neointimal formation. Factors such as the dose used, the duration of the treatment, and the animal model studied may explain discrepancies between studies.

3.1.2 VEGF
VEGF is unique among angiogenic growth factors by virtue of the fact that its high-affinity binding sites (Flt-1 [123]and Flk-1/KDR [84, 124]) are present on ECs, but not other cell types; consequently, the mitogenic effects of VEGF are limited to ECs [83, 125]. A study by Asahara et al. [126]investigated the hypothesis that a single, direct application of VEGF to the intimal surface of a balloon injured artery could accelerate reendothelialization. In this study VEGF (100 µg) was given locally after balloon injury of the rat carotid artery. At 2 weeks and 4 weeks post-balloon injury, the extent of reendothelialization was markedly superior in the VEGF group vs. the control group. Interestingly, neointimal thickening was correspondingly attenuated to a statistically significant degree in those arteries treated with VEGF. In addition, histochemical analyses demonstrated a lower frequency of proliferating cells in the neointima of VEGF-treated animals. This result was supported by the simultaneous demonstration that in the rat carotid model VEGF administration increases EC proliferation after balloon injury in a dose-dependent manner [105]. VEGF thus appears to be as potent as FGF in inducing endothelial regrowth; its specificity for ECs may represent a potential advantage over FGF because the indirect inhibition of VSMC growth by the regenerated endothelium will not be antagonized by direct stimulation.

While similar results were observed by other groups using either local or systemic administration of VEGF [105, 127, 128]a recent report from Lindner et al. [129]did not observe any effect of local VEGF administration on endothelial proliferation and endothelial regrowth in a rat carotid model of balloon injury. This apparent discrepancy may be explained by differences in dose and route of VEGF administration.

More recently, the effects of direct gene transfer of VEGF after angioplasty in a rabbit model have been investigated [130]. In this study, New Zealand White rabbits underwent simultaneous balloon injury and gene transfer with phVEGF165, encoding the 165-amino acid isoform of VEGF. Gene expression was observed as early as 36 hours post-transfection, and persisted for 2 weeks, before diminishing at 3 weeks. A significant increase in the serum concentration of VEGF was observed 5 days after transfection. Planimetric analysis disclosed near complete reendothelialization by 7 days among VEGF-transfected arteries, while the extent of reendothelialization in control arteries was less than 50% complete at 7 days and remained nearly 20% incomplete at 4 weeks. In this study, a complete assessment of the consequences of reendothelialization was performed: (1) Treated arteries disclosed recovery of near normal endothelium-dependent responses within 1 week while control arteries demonstrated persistent impairment in endothelium-dependent responses at 4 weeks post-injury. (2) VEGF-treated arteries had less neointimal thickening and consequently a greater angiographic luminal diameter than control arteries. (3) Thrombotic occlusion developed less frequently in animals transfected with phVEGF165 than in control animals.

All above described studies demonstrate that endothelial growth factors have the potential to accelerate endothelial regrowth in vivo, to improve endothelial dysfunction, and to interfere with intimal growth. It is important to point out, however, that to date no data are available on a potential effect of endothelial growth factors on vascular remodeling.

3.2 Accelerated endothelialization of endovascular stents
Implantation of permanent stents is emerging as an effective treatment strategy for patients with coronary or peripheral artery disease. Recent studies have established stents as the first mechanical device to reduce restenosis after balloon angioplasty [131, 132].

However, even if less frequent, restenosis remains a significant problem after coronary stenting; angiographic restenosis rates varying between 13% and 32% have been reported. Development of restenosis after stent implantation has been attributed principally to intimal growth [133]due to VSMC proliferation and thrombus formation [134], since stents are considered to eliminate any component of arterial remodeling. Subacute stent thrombosis, a troublesome complication in early clinical trials [135, 136], has been reduced in frequency with the advent of high-pressure balloon inflation [137]and by recent changes in antithrombotic regimens [138, 139].

Both of these pathological targets, intimal thickening and thrombosis, have been conceptually linked to the initial absence of an intact endothelial monolayer [140]. Limited and discordant results have been published regarding the process of stent reendothelialization. In rabbit aorta, the process has been described as ‘completed’ after 1 week [141]; for rabbit iliac arteries, it was observed that "after 1 week arteries began to endothelialize" [142], and in dog and pig coronary models, endothelialization has been evaluated as ‘incomplete’ [143]or ‘advanced’ [144]after 1 week. In a series of stents implanted in human venous bypass grafts, no significant endothelialization was observed in three specimens retrieved within 14 days following implantation [145]. In the only published series of human coronary stents examined at necropsy, endothelialization was observed in one of three specimens retrieved 3 weeks after implantation [146].

We have recently investigated whether administration of EC growth factors may accelerate the development of an intact endothelial monolayer after stent implantation. Prior to investigate this issue, we specifically evaluated spontaneous stent endothelialization in a rabbit iliac model. Our analysis indicates that, in a model of balloon injury followed by stent implantation, complete endothelialization in stented arteries <3.0 mm diameter requires, as suggested previously, up to four weeks and that, after 7 days, endothelial coverage of the stented arterial segment is {approx}30% [147].

Subsequent experiments performed in the above described model and using either local delivery of VEGF protein (100 µg) or local gene transfer of the gene encoding for VEGF (800 µg) demonstrated near complete endothelialization of the stented vessel by day 7 [147, 148](Fig. 2). This was associated with an apparent recovery of EC morphology and a decrease in mural thrombus formation [147, 148]. These effects on endothelial coverage and thrombus formation were associated with a significant decrease in intimal growth within the stented segments [148, 149]. The potential for accelerated endothelialization to decrease in-stent intimal growth was further emphasized by a study by Rogers et al. [150]. In this study a conservative strategy of stent implantation, performed without prior balloon injury, was associated with a substantial amount of remnant ECs and allowed an accelerated stent endothelialization and a decrease in intimal growth.


Figure 2
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  		Fig. 2 Effect of local VEGF protein delivery on stent endothelialization: Representative examples of stent endothelialization 7 days after local delivery of vehicle alone (left) or rhVEGF165 (right). Left panels: Top, photomacrograph of the silver stained surface from the middle portion of the stent (x12). No endothelialization is observed in midstent, whereas significant thrombus is visible around the struts. Scanning electron microphotographs from proximal (x300), middle (x1000), and distal (x100) portions of the stent confirm partial endothelialization in the proximal and distal stent, with visible blood cells and thrombus (middle). Right panels: Top, photomacrograph of silver stained surface from middle portion of stent (x8.5). Notice complete endothelialization covering the struts, whereas no significant clots are visible. Scanning electron microphotographs from proximal (x500), middle (x100), and distal (x100) portions of the stent confirm complete endothelialization, with confluent endothelial cell layer covering the stent (middle). Endothelial cells appear to be arranged in direction of flow in proximal and distal stent. (From Van Belle et al. [147]with the permission of the authors.)

 
All above results suggest that accelerated endothelialization may constitute an effective way to prevent both thrombus formation and intimal growth at the site of stent implantation.


   4 Beside growth factors
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 1 The 'normal' endothelial...
 2 Spontaneous endothelialization...
 3 Applied reendothelialization...
 4 Beside growth factors
5 Future prospects
 References
 
Beside administration of EC growth factors, other treatment strategies have been tested to increase endothelial regrowth and/or improve endothelial function after arterial injury in vivo. These strategies include ACE inhibition, administration of estrogen and endothelial cell seeding.

4.1 ACE inhibition
The arterial vessel wall possesses all the components of the renin angiotensin system [22]. Particularly angiotensinogen, renin and angiotensin-converting enzyme (ACE) are present in ECs.

ACE inhibitors are known to inhibit neointimal hyperplasia in different animal models of balloon denudation [151, 152]. This effect has been attributed to the inhibition of the conversion of angiotensin I to angiotensin II or to inhibition of kinin hydrolysis with stimulation of NO release [152, 153].

More recently it has also been demonstrated that, in a rabbit model of balloon injury, ACE inhibitors may improve endothelial dysfunction and simultaneously decrease intimal hyperplasia [154]. Similar effects on endothelial function were observed in other animal models [155]and more recently in human coronary arteries [156].

An effect of ACE inhibition on endothelial regrowth could partly explain the two above effects; reduction of intimal hyperplasia and improved endothelial function; observed in balloon-injury models. ACE inhibition was indeed recently associated with accelerated endothelial regrowth in vivo in a rabbit model of balloon injury [157]. This finding concurs with previous in vitro studies that showed that ACE inhibitors influence proliferation and migration of ECs [158, 159]. There are several potential mechanisms by which ACE inhibition may accelerate endothelial regrowth. First, via inhibition of the conversion of angiotensin I to angiotensin II. Stoll et al. [159]recently reported that angiotensin II inhibits proliferation of basic fibroblast growth factor-stimulated rat coronary ECs in a dose-dependent manner. Similarly, Bell and Madri [158]showed that lisinopril increased migration of bovine aortic endothelial cells in vitro and that exogenous angiotensin II abolished this effect. A second explanation may relate to inhibition of kinin hydrolysis associated with stimulation of NO synthesis. Indeed, it has been suggested that NO may promote proliferation and migration of ECs [160]. Finally, although in vitro studies [158, 159]suggest that the renin angiotensin system may directly influence endothelial regrowth, ACE inhibition could also influence endothelial resurfacing via its hemodynamic effects and the associated changes in blood flow velocity and wall forces. Further studies are needed to elucidate the precise mechanisms of the effects of ACE inhibition on endothelial regrowth.

In addition to a quantitative effect on endothelial regrowth, scanning electron microscopy analysis demonstrated that ACE inhibition had a profound effect on EC morphology. These findings suggest that ACE inhibitors may also have profound effects on EC regeneration apart from mitogenic or migratory effects. Indeed the observed recovery of the spindle shape of the ECs with their long axis oriented in the direction of flow observed in animals treated with ACE inhibitors has been associated with functional recovery of ECs [161](Fig. 3). This observation is in agreement with the previous finding that ACE inhibition improves the functional properties of the neoendothelium [154].


Figure 3
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  		Fig. 3 Effect of ACE inhibition on endothelial regrowth: Representative examples (x1.5) of Evans blue staining 28 days after denudation of one iliac artery in a control (A) and an ACE inhibitor treated animal (B). In controls (A), the reendothelialized (unstained) area, is limited to the mid-portion of the artery around the origin of the internal iliac artery (arrow). In ACE inhibitor treated animals (B), reendothelialization is more extensive, but with a similar pattern. (From Van Belle et al. [157]with the permission of the authors).

 
The quantitative and qualitative impact of ACE inhibition on endothelial regeneration may play a major role in the documented beneficial effects of ACE inhibition on intimal hyperplasia. Indeed, as described above, neointimal thickness is closely related to the presence of a regenerated endothelium [90]. Multiple in vivo studies, using different ACE inhibitors in animal models of balloon arterial injury [152, 154], have documented their inhibitory effects on neointimal hyperplasia. These results suggest that ACE inhibition, beside a blockade of the direct effect of angiotensin II on VSMC growth and/or to potentiation of bradykinin [162], may also indirectly affect neointimal thickening by accelerating endothelial regrowth.

4.2 Estrogen
The inhibitory influence of estrogen on the development of atherosclerosis has been suggested by an abundance of human epidemiological and animal experimental data [163–167]. The expression of estrogen-receptors in ECs [168, 169]suggests a direct effect of estrogen on vascular tissues. This is further supported by the demonstration that estrogen promote survival, proliferation and migration of ECs in vitro [170, 171]. Finally, a positive effect of estrogen on endothelial regrowth was recently reported in a rat carotid model of balloon injury by two different groups [127, 172]. In these studies, the effects of estrogen administration on the endothelium were both anatomic and functional [127, 172, 173]and associated with a decrease in intimal hyperplasia [127, 172]. The mechanism by which estrogen accelerates endothelial recovery in vivo is unknown. Estrogen has been shown to exert direct angiogenic effects on ECs [170]. A potential role for VEGF has been raised by the finding that estradiol induces VEGF mRNA expression in cultured rat VSMCs [172]. It is also of interest to note that the effect achieved with estrogen on reendothelialization is of the same magnitude than that achieved with exogenous administration of VEGF or bFGF [127].

4.3 Endothelial cell seeding
The concept of local delivery of ECs to accelerate endothelial surfacing — a process termed endothelial cell seeding — was first validated in synthetic grafts [174]. This concept was more recently applied to balloon injured arteries [175–179]. In these experiments, autologous [175, 178, 179]or allogeneic [176, 177]ECs were seeded using either a surgical [175, 178, 179]or a balloon-delivery approach [176, 177]. Whatever the technical variations, endothelial cell seeding accelerates endothelial resurfacing of the vessel after balloon injury [175–179]. This strategy has also been shown to decrease platelet deposition [177]; however it failed to prevent intimal thickening [179]. This suggests that EC repopulation alone may not be sufficient to attenuate intimal thickening after balloon injury; modifications of endothelial properties, due to the use of venous cells to seed arterial sites or the requirement for a ‘culture step’ to grow the cells before seeding, may explain this failure. We have to point out, however, that the recent demonstration that autologous endothelial progenitor cells may be isolated from peripheral blood in humans [180]and are incorporated to the luminal surface of denuded artery [181]provide the rationale to investigate alternative methods of cell seeding in order to achieve vascular healing.

A variation of this concept has also been applied to endovascular stents to perform indirect gene transfer and to facilitate improvement of the stent-blood interface [140, 182–184]. This strategy exploits nearly two decades of pioneering efforts to seed prosthetic devices with ECs ex vivo, prior to insertion of the device [140]. The feasibility of preserving transgene expression in transduced ECs applied to metallic stents was originally reported by Dichek et al. [182]. More recently, however, in vivo studies disclosed that sheep venous ECs transduced with a retroviral vector encoding human tissue plasminogen activator in an effort to augment local fibrinolytic activity were prematurely desquamated from the stent surface, possibly due to the effects of local plasmin on EC attachments to the underlying substrate [184]. Whether this unexpected complication is specific for the particular transgene employed in these experiments or whether it applies to all techniques of indirect gene transfer applied to stents remains to be determined.


   5 Future prospects
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 1 The 'normal' endothelial...
 2 Spontaneous endothelialization...
 3 Applied reendothelialization...
 4 Beside growth factors
 5 Future prospects
References
 
One of the remaining questions is which form of delivery — protein or gene — is the most appropriate to achieve endothelial regrowth.

Available data suggest that, because they remain in the vessel wall over a relatively long period of time, the local delivery of heparin binding proteins may be an attractive strategy. The advantages of such a method are its simplicity and safety due to the absence of genetic material involved. However there is limited data to support the use of similar strategy for molecules that do not remain in the vessel wall over a reasonable period, which is the case for most of molecules.

The advantage of gene delivery is the prolonged protein production at the target site (2–4 weeks); it is no longer necessary that the molecule remains in situ to achieve the effect. The main limitation is the low (2–3%, adenoviruses) to very-low (0.1–0.2%, non-viral vectors) transduction efficacy. Thus, to expect an effect, the molecules produced by the transduced cells have to be naturally secreted. In addition, due to the use of genetic material or viral vectors, safety issues arise in the clinical setting.

Nevertheless it is interesting to point out that a phase I human trial has recently been initiated by Professor J.M. Isner in Boston (USA). In this trial the feasibility and safety of local delivery of increasing doses of a plasmid encoding for VEGF165 are being evaluated in patients undergoing balloon angioplasty of peripheral arteries. Since angiography, intravascular ultrasound analysis and Doppler-flow wire measurements are performed at follow-up, information on the effect of this strategy on endothelial function and intimal hyperplasia will be available.

Finally, the recent discovery that circulating endothelial cell progenitors are involved in angiogenesis [180]and endothelial repair after angioplasty [181]will probably constitute the basis for the development of new cell-based strategies to expedite endothelial resurfacing after endovascular injury.

In conclusion, the normal endothelium plays an important role in vascular physiology; its destruction has multiple deleterious effects: increased thrombogenicity, neointimal formation, and abnormal vasomotion. Strategies designed to rapidly restore a functional endothelial layer may thus be beneficial after arterial injury.

Time for primary review 32 days.


   References
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 1 The 'normal' endothelial...
 2 Spontaneous endothelialization...
 3 Applied reendothelialization...
 4 Beside growth factors
 5 Future prospects
 References
 

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