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(Circulation Research. 1995;77:445-465.)
© 1995 American Heart Association, Inc.

Articles

The Intima

Soil for Atherosclerosis and Restenosis

Stephen M. Schwartz, Denis deBlois, Edward R. M. O'Brien

From the Department of Pathology, University of Washington, Seattle.

Correspondence to Dr Stephen M. Schwartz, MD, PhD, Department of Pathology, University of Washington, Vascular Biology/Box 357335, Seattle, WA 98195-7335.

Key Words: intima • atherosclerosis • restenosis

	Introduction

Top Introduction Formation of the Intima Neointimal Formation: A Generic... Pharmacology of Neointimal... Potential Clinical Targets Based... Role of Intima in... Special Properties of... Intimal Cells Overexpress... Mechanisms Controlling Plaque... Pathological Significance of... Mechanism of Lumen Occlusion... The Nature of Restenosis... Relevance of Animal Stenosis... Future Directions References

 
Thirty years ago, John French wrote a seminal review describing the unique properties of the arterial intima.¹ His major point was that the smooth muscle cells of the intima have a unique morphology (Fig 1). French also pointed out that intimal formation appeared during normal development and aging as well as in the response of arteries to almost any imaginable injury, including atherosclerosis.

View larger version (0K): [in this window] [in a new window]   Figure 1. Top left, Histology of intima vs media. Coronary artery is from an adult patient with idiopathic dilated cardiomyopathy. In the absence of atherosclerosis, there remains diffuse intimal hyperplasia. The intima is several cell layers thick and composed of smooth muscle cells and is separated from the distinct media by the internal elastic lamina (arrows) (hematoxylin and eosin, original magnification x200). Top right, Advanced atherosclerosis of the left circumflex coronary artery. This lesion was treated by percutaneous balloon angioplasty 23 days before the patient's death. Note the complex nature of the lesion with a distinct fibrous cap (FC), intimal hyperplasia (IHP), intramural hemorrhage (H), and a necrotic core (NC) composed of inflammatory cells and accumulated lipid (hematoxylin and eosin, original magnification x100). Bottom left, Myxomatous tissue. Directional coronary atherectomy specimen from a restenotic lesion shows stellate-shaped smooth muscle cells. Smooth muscle cells with this appearance are often regarded as evidence of proliferation. Note the homogeneity of these cells and the absence of inflammatory and endothelial cells in this region (hematoxylin and eosin, original magnification x200). Bottom right, Directional coronary atherectomy specimen from a primary lesion. Again, note the presence of stellate-shaped smooth muscle cells but a denser connective tissue matrix (hematoxylin and eosin, original magnification x200).

This article attempts to update French's review. We will discuss the developmental origins of the intima and suggest that the arterial intima is a distinct tissue with a long and rapidly increasing list of differentially expressed genes (Table 1). This pattern of intimal gene expression may be responsible for the origins of atherosclerosis.

View this table: [in this window] [in a new window]   Table 1. Intimal Unique Gene Expression

The bulk of the review, however, deals with the posited role of smooth muscle replication in hypertension, atherosclerosis, and restenosis. Topics covered will include a revisiting of the 20-year-old observation that atherosclerosis is monoclonal^{2 3 4 5} as well as reviews of current knowledge of the pharmacology of smooth muscle proliferation. Perhaps most important, however, we will present a critical discussion of evidence for and against a role for smooth muscle replication in these diseases.

	Formation of the Intima

Top Introduction Formation of the Intima Neointimal Formation: A Generic... Pharmacology of Neointimal... Potential Clinical Targets Based... Role of Intima in... Special Properties of... Intimal Cells Overexpress... Mechanisms Controlling Plaque... Pathological Significance of... Mechanism of Lumen Occlusion... The Nature of Restenosis... Relevance of Animal Stenosis... Future Directions References

 
Surprisingly little is known about how vessels acquire a coat of smooth muscle cells. In the rat, the precursors of the carotid arteries lack a smooth muscle layer as late as day 12 of gestation.⁶ The first smooth muscle cells appear as a condensation around these endothelial tubes over a period of 24 hours. As the mesenchymal cells invest the endothelial tube, the cells begin to express smooth muscle -actin.⁷ Smooth muscle -actin, however, is not a definitive marker of smooth muscle lineage and can be found in many non–smooth muscle cell types.⁸ More definitive smooth muscle–specific proteins are expressed later in development. These include desmin, calponin, smooth muscle -actin, and the smooth muscle myosins.^{9 10 11 12 13} Whereas these latter genes seem largely restricted to smooth muscle cells, their expression is typically lost in cultured cells or in cells that form the neointima.

It is important to realize that not all species go on to form an intima unless their arteries are injured. In humans, the intima develops spontaneously after birth^{14 15 16 17} and increases rapidly until 6 months of age.^{14 17} French suggests that arterial intimal formation is a function of animal size, because arteries of smaller animals do not form an intima unless the vessel first undergoes trauma.¹ The most interesting site of intimal growth is the origin of the left anterior descending coronary artery, a site with a high probability of developing atherosclerosis in later life.

The only site where intimal formation has been well studied is the ductus arteriosus.^{18 19} Contrary to conventional wisdom, this intima forms spontaneously before birth, not as the result of trauma associated with ductus closure. Therefore, it is intriguing to consider ductus closure as a model for diseases of the intima, including atherosclerosis and restenosis.

	Neointimal Formation: A Generic Response of Vessels to Injury?

Top Introduction Formation of the Intima Neointimal Formation: A Generic... Pharmacology of Neointimal... Potential Clinical Targets Based... Role of Intima in... Special Properties of... Intimal Cells Overexpress... Mechanisms Controlling Plaque... Pathological Significance of... Mechanism of Lumen Occlusion... The Nature of Restenosis... Relevance of Animal Stenosis... Future Directions References

 
"Neointima" is an intima that forms in response to injury. We recognize a new intima because many arteries, especially smaller ones, either do not form an intima at all or do so only slowly as the animal ages.^{1 20} Neointimal formation, however, occurs in all arteries as a response to a wide variety of injuries, including radiation, application of turpentine to the adventitia, wrapping the vessel, and electrical stimulation, as well as mechanical injuries, including placement of a suture, scratching with a probe, or dilatation of the common carotid artery with an embolectomy balloon catheter.^{1 21 22 23 24 25 26 27 28 29 30} These changes are even seen in transplanted veins that undergo arterialization. Put another way, neointimal formation is as characteristic of responses to injury in the smooth muscle–rich vessel wall as fibrosis is characteristic of responses in the fibroblastic dermis of skin or gliosis is characteristic of the brain with its glial cells. The most obvious questions about neointimal formation are as follows: (1) Are intimal or neointimal cells, like glia, a distinct cell type? (2) What molecules control neointimal formation? (3) What does neointimal formation after arterial injury tell us about the critical mechanisms underlying arterial pathology in aging, atherosclerosis, or restenosis?

	Pharmacology of Neointimal Formation

Top Introduction Formation of the Intima Neointimal Formation: A Generic... Pharmacology of Neointimal... Potential Clinical Targets Based... Role of Intima in... Special Properties of... Intimal Cells Overexpress... Mechanisms Controlling Plaque... Pathological Significance of... Mechanism of Lumen Occlusion... The Nature of Restenosis... Relevance of Animal Stenosis... Future Directions References

 
The best-studied model of neointimal formation is the response of the rat carotid artery to balloon angioplasty.^{23 26 31 32} This simplicity of the rat model has facilitated kinetic analyses of the smooth muscle response, leading to the definition of four waves describing the smooth muscle cell response to injury and to the identification of molecules playing a role in, or interacting with, each of these waves in rats.^{21 33 34}

The use of the rat arterial response to injury as a model for human atherosclerosis or restenosis, however, should only be considered with caution. First, unlike arteries in larger mammals, the rat carotid artery has only rare intimal cells.^{35 36} Formation of new intima may poorly replicate the response to injury when an intima or even an atherosclerotic lesion already exists.³⁷ Second, although platelet adhesion occurs in injured rat arteries, thrombus formation and leukocyte infiltration are minimal. These important events are prominent after vascular injury in rabbits, swine, and nonhuman primates.^{38 39 40 41} In pig coronary arteries, injury caused by distension with an oversized stent initially causes thrombus formation, followed within a few days by significant macrophage and lymphocyte infiltration and finally by smooth muscle cell migration and proliferation in the intima.⁴² Leukocyte infiltration is also common in rabbit arterial lesions^{43 44} but not in rat lesions.⁴⁰ Unfortunately, little is known about the molecules controlling response to injury in these more complex systems.

In the rat, the balloon injury model begins with complete destruction of the endothelium as well as extensive death of medial smooth muscle cells.³² The first response to balloon injury, called "first wave," consists of medial smooth muscle cell proliferation and begins 24 hours after the injury. In elegant studies, Reidy and colleagues^{45 46} have shown that this wave of replication can be completely accounted for by release of bFGF from dying smooth muscle cells. Despite extensive studies of PDGF as an in vitro mitogen,⁴⁷ studies with infused PDGF, as well as studies with anti-PDGF antibodies, have shown that this molecule is only a weak mitogen for smooth muscle cells in the media of injured arteries.^{48 49 50} However, more limited data suggest that -adrenergic antagonists and Ang II may also control medial replication.^{51 52 53}

Although the first wave has no obvious relation to the later migration and intimal proliferation, several studies with antisense agents directed at cell-cycle genes have shown that inhibition of these initial proliferative events in some as-yet-undefined way leads to a diminution of the final extent of neointimal proliferation. Since the antisense is likely only available in the first few days after injury, these studies suggest long-lasting effects on later events, including migration or intimal proliferation.^{54 55 56 57 58 59 60} The migration of smooth muscle cells across the internal elastic lamina to form the intima constitutes the "second wave." Smooth muscle cells are readily observed on the luminal side of the internal elastic lamina 4 days after injury to rat arteries.³² The duration of migration is not known. Several molecules other than PDGF may contribute to smooth muscle migration, including TGF-ß, bFGF, and, as discussed below, Ang II. The relative contributions of these different molecules are not known, nor do we know whether other molecules are involved.^{46 53 61} PDGF has received attention because of many studies implicating this molecule as a growth factor for cultured smooth muscle.⁴⁷ The main effect of PDGF in vivo, however, is on smooth muscle cell migration and not proliferation.^{49 50 62} Immunoneutralization of endogenous PDGF or depletion of circulating platelets inhibits the development of the intimal lesion in response to balloon injury by inhibiting smooth muscle cell migration toward the intima without a reduction in the frequency of proliferating smooth muscle cells in the media or the intima. In the gentle denudation model, administration of PDGF-BB, which recognizes all isoforms of PDGF receptors, causes a 10- to 20-fold increase in smooth muscle cell migration but no more than a 2-fold increase in smooth muscle cell proliferation.⁴⁸ In vivo dose-response studies show that discrepancies between these in vivo data and the potent mitogenic effects of PDGF on smooth muscle cells in vitro do not reflect inadequate dosage.⁴⁸ As discussed below, we do not know whether PDGF is a mitogen in species other than the rat, as is suggested by studies of PDGF transfected into swine arteries. For that matter, we do not know whether PDGF is mitogenic in the rat at other sites of vascular injury, as is suggested by studies of PDGF infused into the kidney.⁶³

Once smooth muscle cells arrive in the intima of the rat artery, neointimal cells closest to the lumen may replicate for weeks to months.⁶⁴ This replication is called the "third wave." Although we cannot say that any specific molecule has definitively been identified as a third-wave mitogen, a few candidates appear to be present in the intima. For example, PDGF-A chain is overexpressed in the intima and colocalizes with replicating cells. Moreover, when PDGF-B was transfected into swine arteries, there was a marked elevation of replication.⁶⁵ Unfortunately, we do not know whether this PDGF was acting as a growth factor in the usual sense or was mimicking the transforming mechanism of the viral homologue of PDGF, v-sis.^{66 67 68} As already noted, in the rat model PDGF-B will not stimulate replication if infused, nor do antibodies to PDGF suppress third-wave replication.^{49 50 69} Other growth control molecules that appear to be overexpressed in the rat neointima include the Ang II receptor, AT-1, and TGF-ß.^{61 70} IGF-1 is also overexpressed after injury; however, it is overexpressed in the media.⁷¹ The neointima can be stimulated to show a further increase of replication by infusion of several of these molecules. This increased responsiveness to mitogens can be called a "fourth wave" and involves at least TGF-ß, bFGF, and Ang II as agonists.^{45 51 61} Again, PDGF does not appear to be mitogenic in the rat carotid artery model, even at doses that markedly stimulate migration of smooth muscle cells in the second wave.⁴⁸

As the time this review was written, no specific molecular antagonist had been shown to inhibit this replication. Even antibodies to bFGF, which are so effective in inhibiting the first wave, have been shown to be impotent against third-wave replication.⁴⁶ In the absence of inhibitors, Koch's postulate cannot be fulfilled. Therefore, we cannot identify the critical molecules that sustain elevated replication in the third wave.

Although we have emphasized smooth muscle cell mitogens, pathological loss of smooth muscle quiescence could also represent the loss of growth inhibitors. Regeneration of the endothelium inhibits proliferation of the underlying neointimal cells.^{32 64 72} At this time, however, the mechanisms for this inhibition remain incompletely understood. Suppression of neointimal cell growth might be due, for example, to endothelial production of NO. In vitro studies have shown that NO can inhibit replication of cultured smooth muscle cells.⁷³ Administration of large doses of L-arginine aimed at chronically raising NO levels in animals immediately after balloon catheter–induced endothelial denudation have resulted in significant inhibition of neointimal thickening.^{74 75 76} Interestingly, Farhy et al⁷⁷ have reported that L-NMMA, a blocker of NO generation, can partially counteract the suppressive effect of ramipril, an ACE inhibitor, on neointimal thickening after balloon injury in rat arteries.⁷⁷ They speculate that inhibition of neointimal formation by ACE inhibitors may be a result of elevation in the level of bradykinin. Bradykinin is a potent stimulator of NO production and is itself normally degraded by ACE. When administered alone, however, the same dose of L-NMMA did not affect neointimal thickening.⁷⁷ Moreover, Hansson et al⁷⁸ have reported that the cytokine-inducible isoform of NO synthase is chronically expressed at high levels by smooth muscle cells at the denuded surface of the neointimal lesion in the rat injured carotid artery,⁷⁸ an area in which smooth muscle DNA synthesis remains chronically elevated.⁶⁴ In addition, in vitro studies suggest that in the presence of bFGF, NO can actually stimulate DNA synthesis and mitogenesis in smooth muscle cells from the rat aorta in primary culture, whereas a similar treatment causes inhibition of DNA synthesis in the passaged smooth muscle cells.⁷⁹ In summary, we do not have definitive evidence for an endogenous role of NO as an inhibitor of replication of neointimal smooth muscle. Table 2 summarizes the molecules that control the three waves.

View this table: [in this window] [in a new window]   Table 2. Likely Mediators of Neointimal Formation

	Potential Clinical Targets Based on the Rat Model

Top Introduction Formation of the Intima Neointimal Formation: A Generic... Pharmacology of Neointimal... Potential Clinical Targets Based... Role of Intima in... Special Properties of... Intimal Cells Overexpress... Mechanisms Controlling Plaque... Pathological Significance of... Mechanism of Lumen Occlusion... The Nature of Restenosis... Relevance of Animal Stenosis... Future Directions References

 
Angiotensin is of special interest as a mediator of neointimal formation because ACE inhibitors that block neointimal formation in the rat model^{53 80} failed to inhibit restenosis in humans.⁸¹ Exploring the reasons for the failure of clinical trials using an ACE inhibitor requires a brief review of some of the pharmacology of the angiotensin system. The ultimate precursor of Ang II is the plasma protein angiotensinogen, from which renin, a kidney-derived endopeptidase, releases the inactive decapeptide Ang I. The carboxypeptidase ACE then metabolizes Ang I to release active Ang II. As already noted, ACE also contributes to the degradation of bradykinin, a potent endogenous inhibitor of neointimal formation.⁷⁷ Although enzymes other than ACE appear to be able to activate Ang I,⁸² the lack of specificity of ACE inhibitors can be overcome by use of specific inhibitors directed at the angiotensin receptors.^{83 84}

Components of the angiotensin pathway may be found together in the intima or neointima.^{85 86} Although both AT-1 and AT-2 receptors are also present in the normal wall, the principal Ang II receptor, AT-1, is elevated in the neointima.^{70 87} Angiotensinogen, which is available from the circulation, may also be produced by the vessel wall. Rakugi et al⁸⁸ have reported an increase in angiotensinogen gene expression in both the media and the neointima during the first 2 weeks after balloon injury to the rat abdominal aorta. Although the validity of these data may be questioned in view of contradictory in situ hybridization studies from other authors,^{89 90} angiotensinogen mRNA is available locally from perivascular fat. The vessel wall may also contain reninlike activity.⁹¹ Some of this activity may be chymase, a protease found in human mast cells, especially around blood vessels.⁸² ACE itself is made by the medial smooth muscle cells and by the endothelium, the major source of this enzyme.⁹² Rakugi et al⁸⁸ have reported that despite loss of the endothelium, 2 weeks after balloon injury the rat abdominal aorta expresses increased levels of ACE activity as well as increased immunoreactivity for ACE in the neointima. Fishel et al⁹³ also have reported increased ACE activity in the rat injured carotid artery as well as a tissue gradient of ACE expression, with the greatest immunoreactivity in the most luminal cells of the neointima. Upregulation of ACE activity also occurs in dog arteries 30 days after balloon injury.⁹⁴ On the other hand, Viswanathan and colleagues^{70 87} used quantitative autoradiography with iodinated ligands to study ACE expression up to 30 days after injury in the rat carotid artery and thoracic aorta. In these studies, levels of binding to ACE levels per milligram of tissue were similar in neointimal lesions devoid of endothelium 15 or 30 days after injury compared with sham arteries with endothelium. Thus, after balloon denudation, there may be no loss of ACE activity, since neointimal ACE replaces the ACE normally produced by the endothelium.

In summary, a possible role for the renin-angiotensin system is supported by evidence for the expression of ACE and other components of the angiotensin system in the injured vessel wall. First-wave replication, migration into the intima, and intimal thickening can be prevented by angiotensin receptor agonists directed against the AT-1 receptor.^{83 84} ACE inhibitors and receptor antagonists seem to block migration as well.^{83 84} These effects are likely mediated by the AT-1 receptor. One report of inhibition by an AT-2 receptor ligand molecule required that the drug be given locally at very high doses.⁹⁵ Thus, it is quite reasonable to interpret the effects of ACE inhibitors in blocking neointimal formation as being in large part the result of blocking formation of Ang II.⁸⁰

The clinical trials may have failed for several reasons. First, the effects of ACE inhibitors may be determined by genetic variation in the population. Ohishi et al⁹⁶ recently found a striking correlation between restenosis and an isoform of ACE. This isoform, a deletion, had previous been identified by Cambien et al⁹⁷ as a risk factor for myocardial infarction. Second, it is important to note that ACE inhibitor doses used in the clinical trials were ineffective in the rat studies as well as in trials after arterial injury in swine and nonhuman primates.^{98 99 100} Effective doses in animal studies were hypotensive,⁸⁰ possibly because of the elevated levels of bradykinin discussed above. Such doses would not be acceptable in humans. Third, as already noted, ACE is not the only enzyme able to generate Ang II in humans. Chymase is present in human plaques and cannot be inhibited by the converting enzyme inhibitors.^{82 101} Chymase activity is also dramatically upregulated 30 days after balloon injury in dog arteries.⁹⁴ Other potential alternative pathways for the activation of Ang II also include serine proteases, such as leukocyte-derived tonin,¹⁰² and carboxypeptidases from human platelets¹⁰³ or from the tunica media.¹⁰⁴

The PDGFs are also of special clinical interest because of the emphasis on these molecules in the "response to injury" hypothesis.⁴⁷ We have already noted that in contrast to FGF or Ang II, infused PDGF-BB seems to function primarily in promoting migration.^{48 49 50} The absence of a mitogenic effect in the rat model, of course, does not rule out an effect in humans. As already discussed, transfected PDGF-BB was mitogenic in swine. Moreover, again in the rat, the production of PDGF-B by cultured smooth muscle cells does correlate with an enhanced ability to grow without serum-derived growth factors.^{105 106} We have recently found that 10% of the most superficial cells in the neointima express PDGF-B chain, as demonstrated by in situ hybridization.¹⁰⁷ It is intriguing to think that the subset B chain–positive cells in vitro are the ancestors of the characteristic B chain–positive cells seen after passage in vitro. We do not know whether similar cells might exist in proliferative regions of human restenotic tissue.

PDGF-A chain is also of interest, despite the observation that PDGF-A is itself a nonmitogen or a weak mitogen in vitro.⁴⁸ This molecule is chronically overexpressed by smooth muscle cells in the neointima in the rat model⁶⁹ and in atherosclerotic plaques in humans.^{108 109} A recent immunocytochemical study colocalized PCNA, a marker for cell replication (see below), with PDGF-A chain.¹¹⁰ The mitogenic effect of a number of mild mitogens, including bFGF, TGF-ß, and Ang II, has been shown to be substantially blocked in vitro by antibodies to PDGF-A.⁴⁹ Thus, we need to consider the possibility that the localized overexpression of PDGF-A seen in the neointima may act as a cofactor that increases the fourth-wave responsiveness to other growth factors.

TGF-ß may also play an important role in third- and fourth-wave replication. As already noted, there is an accumulation of TGF-ß in the neointima,⁶¹ and we found that infused TGF-ß was a neointimal mitogen. More recently, Nabel et al¹¹¹ found augmented neointimal hyperplasia in a swine model after injury and transfection with a TGF-ß plasmid. Similarly, Wolf et al¹¹² found that neointimal formation in the rat model was inhibited by antibodies to TGF-ß. Finally, a recent study of atherectomy specimens found elevated levels of TGF-ß in restenotic lesions.¹¹³

These in vivo data contrast with the recent proposal by Grainger and colleagues¹¹⁴ that TGF-ß in humans is an inhibitor of atherosclerosis. The Grainger hypothesis is based on studies in vitro in which TGF-ß is sometimes seen as a growth stimulant and at other times as an inhibitor. This variability may reflect the strain of smooth muscle cells studied and their state of confluence.^{115 116 117} Grainger et al¹¹⁴ emphasize the inhibitory effects and attempt to link endogenously produced TGF-ß with elevated atherosclerosis risk due to elevated Lp(a). Although Lp(a) is well known as a risk factor for atherosclerosis, a recent study suggests that Lp(a) levels also correlate with an increased incidence of restenosis.^{118 119} As a homologue of plasminogen, the apoprotein of Lp(a), called Apo(a), is believed to inhibit the formation of plasmin.^{120 121} Plasmin, in addition to its role in fibrinolysis, is essential to the activation of TGF-ß.¹²² Grainger and colleagues^{114 123 124 125} found that Apo(a) is mitogenic for smooth muscle cells in culture and were able to attribute this mitogenesis to inhibition of the formation of plasmin and the subsequent inability of the cells to activate TGF-ß. In this view, the predominant role of TGF-ß would be as an endogenous inhibitor of lesion formation at sites of active coagulation, and Apo(a) would enhance lesion formation by diminishing the production of activated TGF-ß.

Thrombin is another neointimal molecule that is attracting renewed interest because of the recent cloning of a thrombin receptor and the recognition that thrombin can have a direct mitogenic effect on cells independent of the coagulation cascade.^{126 127} Particularly intriguing is the evidence that thrombin activity is chronically elevated in the neointima and that the neointima, as well as human atherosclerotic plaque, overexpresses the thrombin receptor.^{128 129 130} In addition, studies involving animal model systems more complex than the rat, especially the pig coronary artery stent model, suggest that thrombosis may well play a key role in the early events leading to restenosis.⁴²

The last three molecules for this discussion are somatostatin, heparin, and the integrins associated with thrombosis and vascular responses to injury. Somatostatin analogues and heparin-like compounds are of special interest because of the extensive studies of their ability to inhibit neointimal formation in animal models. Somatostatin analogues, in particular, angiopeptin, have been found to be effective in a range of animals species and different models of arterial injury, including fat feeding, balloon angioplasty, neointimal formation in vein grafts, and transplant atherosclerosis.^{131 132 133 134 135} Clinical trials are under way, but preliminary results appear to be equivocal.¹³⁶ The pharmacological rationale for this approach is unclear; however, it is important to note that somatostatin receptors are widespread in the body and may act as vasodilators or vasoconstrictors in blood vessels.^{137 138 139 140} Failure or success of angiopeptin trials to prevent restenosis will be especially important, because the dosages of the drug that were used in humans were comparable to those used in animals.

Similarly, heparin has been widely studied as an inhibitor of intimal formation in animal models.¹⁴¹ As with somatostatin, the mechanism of action of heparin as an inhibitor of intimal hyperplasia is poorly understood. Although much attention has been focused on the potential role of heparin on c-myb, this molecule is expressed in the late G1 phase of the cell cycle and likely represents only one of several defects when growth is inhibited.¹⁴² Equally intriguing are the role of heparin in inhibiting migration and suggestions from Lindner and Reidy⁴⁵ that a major action of heparin may be to wash bFGF out of the injured vessel wall after the mitogen is released from dying cells. Unfortunately, clinical trials using heparin to prevent restenosis have been disappointing.^{143 144} Ellis et al¹⁴³ administered intravenous heparin to patients over the first 18 to 24 hours after angioplasty and found no difference in the restenosis rates of patients treated with heparin compared with those given a dextrose infusion (41% versus 37%, respectively; P=NS). Similarly, a subsequent attempt to limit restenosis with a single daily subcutaneous injection of 10 000 IU heparin was halted prematurely because of the higher rates of restenosis and clinical events in the heparin treatment group compared with the usual care group.¹⁴⁴ This lack of clinical benefit is difficult to explain but may be related to a rebound coagulation phenomenon associated with interrupted anticoagulant treatments.¹⁴⁵ Edelman and Karnovsky¹⁴⁶ suggest that differences in heparin dose scheduling may be critical. For example, the antiproliferative effect of heparin requires that the drug be administered for at least 4 to 7 days after injury in the rat carotid balloon injury model.³² Furthermore, cell proliferation and the ratio of the intimal to medial area are made worse when rats are treated with heparin dosages and administration schedules similar to those used clinically.¹⁴⁶ Low-molecular-weight heparins also appear to be ineffective for the prevention of restenosis.¹⁴⁷

The failure of antiproliferative therapies based on angiotensin, somatostatin, and heparin may be telling us that we should consider other mechanisms as being critical to restenosis. A clue as to such mechanisms may have arisen serendipitously from a recent clinical trial directed at the thrombotic events occurring immediately after angioplasty. As part of the EPIC study, the chimeric monoclonal antibody Fab fragment (c7E3), which is directed against the platelet glycoprotein IIb/IIIa receptor, was administered to patients undergoing angioplasty or atherectomy who were at high risk for ischemic complications.^{148 149 150} This therapy resulted in a reduction in acute ischemic complications (eg, nonfatal myocardial infarction and emergency revascularization procedures), although at the risk of increased bleeding complications. Although it is easy to imagine that these trials are affecting only platelets, these antagonists to glycoprotein IIb/ IIIa, a platelet adhesive protein, may also affect a closely related integrin, _vß₃. Antagonists to _vß₃ have recently been shown to block smooth muscle migration in vitro and intimal formation in vivo.¹⁵¹ Moreover, we have found that this same receptor is required for movement of smooth muscle cells in response to osteopontin, an abundant and specific marker of intimal smooth muscle cells in the rat¹⁵² and in human plaque.^{153 154} Therapies targeted against integrin receptors involved in platelet aggregation and cell migration represent an intriguing new direction.

	Role of Intima in the Formation of an Atherosclerotic Lesion

Top Introduction Formation of the Intima Neointimal Formation: A Generic... Pharmacology of Neointimal... Potential Clinical Targets Based... Role of Intima in... Special Properties of... Intimal Cells Overexpress... Mechanisms Controlling Plaque... Pathological Significance of... Mechanism of Lumen Occlusion... The Nature of Restenosis... Relevance of Animal Stenosis... Future Directions References

 
Stary et al¹⁵⁵ note that the initial lipid accumulation occurs deep in the wall, within the preexisting intimal mass. The intimal mass is not defined as atherosclerosis, since it has not yet accumulated lipid and is seen as a normal feature of vessels in our species. Aside from such semantic issues, localization and initiation of atherosclerosis in intimal masses are reminiscent of experiments in balloon-injured animals in which lesions develop selectively at sites of previous injury and intimal formation.³⁷ Thus, atherosclerosis may begin in the "soil" of the intima. The peculiar properties of the intima that lead to such a phenomenon have not been identified. However, there have been suggestions that local accumulations of specific glycosaminoglycans related to chondroitin sulfate may promote local lipid accumulation.^{156 157}

The time course of intimal smooth muscle proliferation in relation to lipid accumulation in humans is not known. Ross^{47 158} has suggested that proliferation of smooth muscle cells is important in advanced lesions. This idea, however, is not supported by cell kinetic studies measuring either the frequency of cells able to incorporate labeled thymidine ex vivo or the number of cells identified as replicative on the basis of staining for a cell cycle–specific marker.^{159 160} The low replicative rates seen in advanced lesions correlate with studies of cells cultured from lesions. Moss and Benditt¹⁶¹ were the first to culture these cells. They found that plaque smooth muscle cells have a greatly shortened life span relative to normal medial cells. This observation has been reproduced by others.^{162 163} More recently, we have extended this observation by looking at apoptosis. Plaque smooth muscle cells, at least in vitro, have a very high rate of spontaneous cell death. This high level of apoptosis may account for the apparent short replicative life span and suggests that plaque cells have undergone some as-yet-undefined injury in vivo.¹⁶⁴

Interestingly, the only actual evidence that smooth muscle proliferation occurs in atherosclerosis depends on evidence that the lesions are monoclonal or oligoclonal. The original observation of clonality by Benditt and Benditt⁵ has been reproduced by two other groups.^{2 3 4} It is difficult to imagine how clonality could arise unless proliferation plays a critical role in an event at some time in the ontogeny of the lesions.

Hansson et al¹⁶⁵ have recently shown that lymphocytes in lesions are polyclonal. The remaining cells in these lesions are macrophage, smooth muscle, and endothelial cells. Although plaque macrophage and endothelial cells do replicate,^{159 166} there are no known examples of these cell types forming monoclonal growths other than in neoplasms.^{47 159} Thus, monoclonality implies that smooth muscle proliferation must occur during the formation of the lesion and that the initial group of cells giving rise to the lesion must be very small. Such an early expansion of intimal smooth muscle mass has been described exactly to occur in the proximal left anterior descending coronary artery, a common site for occlusive coronary artery lesions in adults.^{14 17} If the increase in mass described in the newborn left anterior descending coronary artery correlates with smooth muscle replication, then very few further doublings may be required to account for the mass of smooth muscle seen in an adult lesion.

In summary, the available direct evidence suggests that smooth muscle replication occurs very early in the formation of atherosclerotic lesions.^{14 17} We cannot rule out the possibility that smooth muscle replication occurs at a very low rate over several years or that replication occurs at a high rate in an episodic fashion.

	Special Properties of Atherosclerotic Intima

Top Introduction Formation of the Intima Neointimal Formation: A Generic... Pharmacology of Neointimal... Potential Clinical Targets Based... Role of Intima in... Special Properties of... Intimal Cells Overexpress... Mechanisms Controlling Plaque... Pathological Significance of... Mechanism of Lumen Occlusion... The Nature of Restenosis... Relevance of Animal Stenosis... Future Directions References

 
Whether or not the atherosclerotic plaque is hyperproliferative, the lesions are progressive, and it seems obvious that progression must depend on unique properties either of the intima or of the plaque itself.¹⁶⁷ Table 1 is an attempt to collate those properties with special regard to genes that are underexpressed or overexpressed by the intimal or plaque smooth muscle cell relative to medial smooth muscle cells. This table emphasizes rat and human data, the species about which the most is known. Some rabbit data are also included. In addition, the table includes data from cultured smooth muscle cells, since the preservation of properties in vitro identifies intimal smooth muscle cells that may be differently differentiated from medial smooth muscle cells.

Table 1 also lists a large number of molecules whose expression is characteristically decreased by intimal cells compared with medial cells. Loss of expression of the genes associated with the fully differentiated, "contractile" phenotype was first described by Campbell and Campbell¹⁶⁸ and has been confirmed by others.^{169 170 171} Campbell and Campbell have given the change from a contractile to a "synthetic" phenotype the name "modulation." The term synthetic is used because cultured cells lose much of their microfilaments and, as seen by transmission electron microscopy, acquire an extensive rough endoplasmic reticulum. Because modulation coincides with the onset of replication in vitro, several workers have proposed that special properties of the modulated smooth muscle cell may include proliferation and synthesis of matrix molecules that contribute to formation of the intima and the plaque.^{168 169 170 171} Molecules lost in modulated cells include smooth muscle myosin, desmin, caldesmon, and -actin.^{10 172}

Unfortunately, the term synthetic has been loosely applied to cells lacking a smooth muscle phenotype, because intimal cells as well as many cells in the media may lack the contractile phenotype without showing evidence of an active synthetic apparatus^{169 173} (D. Gordon and S.M. Schwartz, unpublished data involving the internal mammary artery, 1994). Inversely, smooth muscle cells can rapidly leave quiescence in the vascular wall after balloon injury, enter S phase, and still express abundant -actin mRNA.¹⁷⁴ Thus, the equation of synthetic phenotype with replication is unconvincing. Similarly, the media of avian aortas contains a second cell type that, while apparently quiescent, lacks morphological features of the contractile smooth muscle cell.^{175 176 177} Thus, loss of the contractile phenotype should be distinguished from the onset of proliferation or change to a phenotype associated with high levels of protein synthesis.

An excellent example of the difference between a vessel with only a media and one with an atherosclerotic intima is the issue of vascular contractility. Normally, the vessel wall exists in a relaxed state due to the endogenous production of NO by endothelium. NO-dependent relaxation, however, is greatly impaired in atherosclerotic vessels.¹⁷⁸ This loss of function is not due to a change in the smooth muscle of the media. Loss of NO function has been attributed to endothelial injury or to the inactivation of NO by free radicals produced in the plaque.¹⁷⁹ In contrast, Joly et al¹⁸⁰ described the appearance of the inducible form of NO synthase that follows balloon injury. Similarly, as described above, the neointima overexpresses angiotensin receptors, and the plaque has been shown to overexpress endothelin.¹⁸¹ Although we have not yet distinguished the effects of atherosclerosis from those of the more general appearance of the neointima, our point is simply that we might expect the vasomotor activity of a diseased artery with an intima to be very different from vasomotor regulation in a normal artery. The contribution of this altered pharmacology to the ability of the vessel wall to maintain a normal lumen caliber is largely unexplored.

In summary, Table 1 points out that intima and media are quite different tissues. At least some genes are overexpressed in the intima, even in the absence of atherosclerosis; for example, the human intima overexpresses the ß1 chain of laminin and the ED-A splice form of fibronectin.^{182 183} In the rat, a large number of genes are overexpressed after injury, but so far only tenascin has been shown to be overexpressed in the few intimal cells seen in the normal rat artery.^{184 185} Tenascin, ß1 laminin, and ED fibronectin are important, since their expression suggests that intimal smooth muscle cells rather than merely lacking the properties of medial smooth muscle may have their own unique properties. We have already discussed the possible significance of overexpression of NO synthase, AT-1 angiotensin receptors, proteoglycans, PDGF, or TGF-ß in the ontogeny of smooth muscle proliferation and lipid accumulation. Differences in NO metabolism¹⁸⁶ or AT-1 receptors,⁸⁷ to cite just two markers, are likely to mean that vessels with an intima have very different pharmacology than vessels with only a media. A critical issue, as we will see below, is whether the unique properties of intimal cells represent a unique cell type with heritable properties that distinguish intimal smooth muscle from medial smooth muscle.

	Intimal Cells Overexpress Certain Genes In Vitro as Well as In Vivo

Top Introduction Formation of the Intima Neointimal Formation: A Generic... Pharmacology of Neointimal... Potential Clinical Targets Based... Role of Intima in... Special Properties of... Intimal Cells Overexpress... Mechanisms Controlling Plaque... Pathological Significance of... Mechanism of Lumen Occlusion... The Nature of Restenosis... Relevance of Animal Stenosis... Future Directions References

 
Cell culture studies suggest that intimal cells may be differentiated from the typical medial smooth muscle cell. Smooth muscle cell lines cultured from 2-week-old rat pups have several unique properties. These include an epithelioid morphology, the ability to grow without platelet-released growth factors, and secretion of PDGF.^{187 188} These same properties appear when neointimal cells, isolated 2 weeks after arterial injury, are placed in culture.¹⁰⁵ When the same cells were studied for gene expression, a group of genes was found that shows overexpression or even unique expression in pup and intimal cells compared with normal medial cells cultured from adult arteries.^{187 189 190} This collection of properties and genes led us to suggest that the vessel wall, at least in the rat, contains two types of cells: and µ cells. Genes overexpressed by cells include PDGF-B chain, CYPIA1, elastin, and osteopontin.^{187 189 190}

Unlike the distinction between contractile and synthetic phenotypes, which is lost when all cells put in culture become synthetic, the differences between the µ phenotype and phenotype seem to be maintained in passage, and cells with or µ properties can be isolated by cloning cells from mixed cultures.^{191 192} Moreover, some of these genes, although first identified in vitro, are also overexpressed or uniquely expressed in the neointima in vivo. At least for the rat, we suggest that smooth muscle cells contain two distinct "cell types," one of which takes a special part in the formation of the neointima.

Comparable evidence has not yet been discovered for subsets in human smooth muscle. Cultured human fetal smooth muscle cells also differ from adult smooth muscle cells in their expression of two homeobox genes, HoxB7 and HoxC9. These genes are also seen in pup cells but not in rat cells, however. HoxB7 and HoxC9 are not seen in human intima or atherosclerotic plaques (J.M. Miano, A.B. Firulli, E.N. Olson, P. Hara, C.M. Giachelli, S.M. Schwartz, unpublished data, 1994). However, as already noted, human intima preserves certain genes that are also seen in the fetal vessel.¹⁰ Moreover, if atherosclerotic lesions are monoclonal, the origin of lesions in the intima suggests that lesions are derived from a unique subset of vessel wall smooth muscle cells localized to this layer.⁵

	Mechanisms Controlling Plaque-Specific Gene Expression by Smooth Muscle Cells

Top Introduction Formation of the Intima Neointimal Formation: A Generic... Pharmacology of Neointimal... Potential Clinical Targets Based... Role of Intima in... Special Properties of... Intimal Cells Overexpress... Mechanisms Controlling Plaque... Pathological Significance of... Mechanism of Lumen Occlusion... The Nature of Restenosis... Relevance of Animal Stenosis... Future Directions References

 
Overexpression of certain molecules by intimal cells might be the result of two quite different, but not necessarily independent, mechanisms. First, as suggested above, intimal cells might belong to a unique lineage either derived from a common precursor or differentiated from typical smooth muscle cells. The detection of stable and µ phenotypes in vitro supports this hypothesis. Alternatively, and more obviously, plaque cells may show overexpression or repression of certain molecules as a result of mediators present in the plaque environment. Particularly important among such mediators are oxidation products or more traditional inflammatory mediators.^{193 194} Collins¹⁹⁵ has suggested that a common factor linking inflammation and oxidation is the role of nuclear factor-B as a trans-acting factor induced by oxidized radicals and by many cytokines.¹⁹⁵ Table 1 includes plaque-specific genes whose overexpression might be explained as an inflammatory response. In some cases, however, this may be misleading, since overexpression in the plaque is permanent, whereas overexpression in response to cytokines is often only transient. Distinguishing between extrinsic and endogenous controls of gene expression is likely to depend on cell culture results showing stable expression, as is evident for some genes in Table 1, as well as promoter analyses taking place in the individual labs.

	Pathological Significance of Plaque-Specific or Intimal-Specific Genes

Top Introduction Formation of the Intima Neointimal Formation: A Generic... Pharmacology of Neointimal... Potential Clinical Targets Based... Role of Intima in... Special Properties of... Intimal Cells Overexpress... Mechanisms Controlling Plaque... Pathological Significance of... Mechanism of Lumen Occlusion... The Nature of Restenosis... Relevance of Animal Stenosis... Future Directions References

 
Among the more interesting genes shown to be overexpressed in plaques are tissue factor, MCSF, GMCSF, osteopontin, and bone morphogenic protein.

Tissue Factor
The normal arterial wall contains little or no tissue factor. The time course for the appearance of tissue factor in plaques is not known, however. Tissue factor is prominent in cells of the plaque, including smooth muscle cells. Davies and Thomas¹⁹⁶ and others^{197 198 199 200} have suggested that thrombosis is a critical event in plaque progression. Thus, it is likely that accumulation of tissue factor is critical to the morbidity of lesions. Moreover, Taubman²⁰¹ has shown that tissue factor mRNA expression was elevated after balloon injury in rats. This was not surprising, since tissue factor was known from in vitro studies to be a component of the early phases of the cell cycle. Perhaps more surprisingly, he found an elevation of tissue factor activity, implying that a procoagulant response is part of the formation of neointima.

MCSF/GMCSF
The presence of leukocyte growth factors MCSF and GMCSF as well as receptors for leukocyte factors (see Table 1) is of special importance because of growing evidence that plaque macrophage, rather than plaque smooth muscle cells, may constitute the major unique proliferative element in the plaque.^{159 160} The unique properties of the proliferative plaque macrophage have yet to be explored.

Osteopontin and Bone Morphogenic Protein
Osteopontin and bone morphogenetic protein 2a have both been found in smooth muscle cells of atherosclerotic plaques.^{154 202 203} The presence of these molecules is supportive of the hypothesis that plaques are derived from unique subsets of smooth muscle cells, because osteopontin was first found in neointimal cells and in the rat pup artery as part of the phenotype.¹⁹⁰ Bone morphogenetic protein 2a, on the other hand, is also seen only in plaques. Intriguingly, cells found to express bone morphogenetic protein 2a also express immunocytochemical markers associated with a special form of smooth muscle cell, the pericytes seen around small vessels, again suggesting a unique lineage for plaque smooth muscle compared with medial smooth muscle.²⁰³ The association of osteopontin and bone morphogenetic protein 2a with areas of calcification in the plaque also suggests that the mechanisms of bone mineralization may also play a role in vessel wall calcification.

	Mechanism of Lumen Occlusion in Atherosclerosis

Top Introduction Formation of the Intima Neointimal Formation: A Generic... Pharmacology of Neointimal... Potential Clinical Targets Based... Role of Intima in... Special Properties of... Intimal Cells Overexpress... Mechanisms Controlling Plaque... Pathological Significance of... Mechanism of Lumen Occlusion... The Nature of Restenosis... Relevance of Animal Stenosis... Future Directions References

 
Vascular lumen size can be regulated either by rapid changes in smooth muscle tone or by structural rearrangement of cells and extracellular matrix components of the wall. The latter mechanisms include "remodeling" and "elastic recoil." For example, Glagov et al²⁰⁴ noted that human vessels can undergo massive accumulations of atherosclerotic mass without lumen narrowing. The vessel compensates for the new mass by undergoing a compensatory redistribution of vessel wall mass so that lumen size is maintained. This remodeling permits a normal level of blood flow until an adaptational limit is exceeded. This limit appears to occur when 40% or more of the area bounded by the internal elastic lamina is occupied by intimal mass. Decreased lumen size in atherosclerosis may depend on pharmacological mechanisms associated with the neointima or the plaque that cause a failure of normal remodeling events. In contrast, elastic recoil, an expression often used to describe the rapid loss of lumen gain after angioplasty, describes the resistance of the vessel wall component to the mechanical stretch imposed by the inflated balloon catheter.

Remodeling is a normal response that allows the vessel to maintain normal levels of blood flow and wall stress and can be seen in small muscular arteries as well as in large elastic arteries.^{205 206} Branching patterns of conduit vessels seem to be genetically determined.²⁰⁷ Thus, the only way arteries can respond to a demand for an increase or a decrease in blood flow is by changing vessel caliber. These changes, in some cases, occur by rearrangement of existing vessel wall components rather than synthesis of new mass or cell replication.²⁰⁸

Despite the observations of Glagov et al²⁰⁴ of arterial remodeling during atherogenesis in human coronary arteries (above), remodeling has been largely ignored in animal models of arterial injury and repair. The extent of remodeling versus loss of lumen due to intimal formation is illustrated by an important experiment by Jamal et al.²⁰⁶ When Jamal et al balloon-injured the rabbit carotid artery, they found the expected neointimal hyperplasia. However, the animals showed no narrowing of the lumen despite a 100% increase in total wall thickness attributable to the neointima. In contrast, the same study showed a significant (14%) narrowing in response to an experimental restriction of flow in the vicinity of the thyroid artery where endothelium had regenerated. This effect of the endothelium in an injured vessel is consistent with observations that structural adaptation to changes in flow requires an endothelium.²⁰⁶ Since reendothelialization generally correlates with a diminution of intimal thickening, these data may even imply a negative correlation of intimal mass with luminal narrowing.⁷²

The role of the endothelium in controlling lumen size may be especially important given the often neglected fact that plaques have a prominent microcirculation that comprises capillaries arising from the adventitia.^{209 210 211} The role of these small vessels in regulating structural change or, for that matter, contractile properties of the atherosclerotic vessel remains unexplored.

If the correlation of intimal (or plaque) mass with lumen caliber is not a simple one, how do we account for angiographic changes seen after aggressive lipid-lowering therapy?^{212 213 214} It is important to realize that the reported clinical benefit of these studies far exceeds the improvement of stenosis diameter. The improvement in lumen size in these studies is very small (eg, 0.7% to 5.3%, or an increase of 0.003 to 0.117 mm in minimum absolute diameter).^{212 214} To put these results in perspective, one should note that 6 months after percutaneous coronary angioplasty, there is an average improvement of 16% diameter stenosis units and a 0.47-mm increase in minimum absolute diameter.²¹⁵ Moreover, even these modest changes in lumen diameter could reflect changes in adherent thrombotic material or state of vasospasm rather than a decrease in mass of the atherosclerotic intima.²¹⁶ Rather than opening the lumen, lipid-lowering therapies may improve clinical outcome by stabilizing the lesion.²¹⁷ Davies and colleagues^{196 218 219} and others^{199 200} have suggested that the formation of fissures in plaques is the critical step leading to vascular occlusion. Davies' hypothesis would imply that we may be able to develop diagnostic tests, based on plaque composition as assessed by magnetic resonance imaging, IVUS, or even gene expression patterns in atherectomy specimens, that might indicate lesion prognosis or the effectiveness of drugs targeted at stabilizing the lesion.

These same tests may allow us to estimate changes in vessel wall mass much as the advent of roentgenography led to estimates of tumor cell growth. The ability to study the progress of human lesions may be critical to our understanding of how lesions progress and eventually kill. Animal models with advanced disease are rare, with the exception of the spontaneously hypercholesterolemic swine.²²⁰ Autopsy data in humans are also confusing. Serial angiographic studies in humans suggest that the majority of myocardial infarctions may occur because of thrombotic occlusion of arteries that previously did not contain hemodynamically significant stenoses (eg, <50%).^{221 222} However, postmortem studies do not bear this out. For example, Qiao and colleagues^{223 224} have reported that in both native coronary arteries and saphenous venous bypass grafts, atherosclerotic plaque rupture with thrombosis most commonly occurred at sites with severe narrowing (eg, >90% area stenosis).

	The Nature of Restenosis Following Angioplasty

Top Introduction Formation of the Intima Neointimal Formation: A Generic... Pharmacology of Neointimal... Potential Clinical Targets Based... Role of Intima in... Special Properties of... Intimal Cells Overexpress... Mechanisms Controlling Plaque... Pathological Significance of... Mechanism of Lumen Occlusion... The Nature of Restenosis... Relevance of Animal Stenosis... Future Directions References

 
Fig 2 shows the tissue that characterizes coronary artery restenosis as seen in atherectomy specimens or at autopsy. Despite use of the word "proliferative" by pathologists to describe this tissue,²²⁵ as we have already suggested, it may be entirely incorrect to assume that the formation of a neointima in a balloon-injured rat carotid artery is a model for the loss of arterial caliber seen after angioplasty, ie, "restenosis."

View larger version (34K): [in this window] [in a new window]   Figure 2. Panels illustrate two phenomena that are often assumed to be equivalent. Top, Result of a typical experimental balloon injury to a normal artery. The vessel is dilated, the media is injured, and an intima is formed. The most important result, however, is stenosis. We would define stenosis as loss of the original lumen size. Bottom, Result when a typical human atherosclerotic vessel undergoes angioplasty. In this case, the vessel is already stenotic. The balloon dilates the vessel to a lumen size assumed to be normal on the basis of a comparison with a reference vessel (usually the same artery upstream of the lesion). The angioplasty fails if the vessel simply heals, ie, returns to its preangioplasty dimension. Rather than a true stenosis, as defined above, restenosis may be thought of as a failure to remain dilated. As described in the text, we have assumed that restenosis includes a large component of intimal hyperplasia. As shown in this figure, recent cell kinetic and ultrasound studies suggest that restenosis may occur without any requirement to form new mass. Put another way, an atherosclerotic vessel that fractured during angioplasty would be considered restenotic if the fracture, like most wounds, healed. Human coronary arteries that are treated by angioplasty already have severe atherosclerotic disease and a preexisting stenosis. Clinical angioplasty produces a larger lumen; however, in 30% to 50% of these lesions, restenosis develops as the arterial lumen renarrows.

We have used immunocytochemical labeling for the PCNA^{159 226} to determine the proliferative profile of 100 restenotic coronary atherectomy specimens.²²⁷ To our surprise, the vast majority of the restenotic specimens (74%) had no evidence of PCNA labeling. Moreover, in those specimens with proliferation, only rare PCNA-positive cells were present, and there were no differences in the frequency of PCNA-positive cells in restenotic specimens collected in the first 3 months, 4 to 6 months, 7 to 9 months, or >9 months after the initial interventional procedure. Furthermore, only 12 of 30 specimens obtained within 60 days of the initial coronary interventional procedure had one or more PCNA-positive nuclei per slide (including nine specimens collected within 6 days of the initial procedure, only three of which had immunolabeling of 1, 7, and 20 cells per slide). A similar study using in vitro bromodeoxyuridine labeling also found low levels of proliferation in restenotic atherectomy specimens,²²⁸ and Strauss et al²²⁹ found no PCNA-positive cells in atherectomy specimens from seven restenotic stented coronary artery lesions. In contrast to these studies of replication in restenotic coronary atherectomy tissue, Rekhter et al,²³⁰ using the same methodology, found PCNA immunolabeling of rapidly stenosing human arteriovenous hemodialysis arteriovenous fistulas to be high. These three studies of restenosis suggest that the response of human atherosclerotic coronary arteries to balloon angioplasty lacks the proliferative first wave seen in the rat model. If this is true, we may not expect clinical trials of drugs directed at the first wave to be successful.⁵⁴

Our results and those of Strauss et al²²⁹ contrast with a recent report by Pickering et al.²³¹ All restenotic coronary and peripheral arterial specimens had surprisingly high percentages of cells that were considered PCNA-positive; eg, as high as 59% of cells were PCNA-positive, comparable to values in malignant neoplasms.²³² Surprisingly, given the very high values, none of these specimens were obtained within 1 month of the initial interventional procedure. It is unlikely that mean PCNA labeling indices of 15% to 20% are physically possible in atherosclerotic coronary arteries, where small changes in vessel wall mass can result in dramatic changes in residual luminal diameter. Although we assume that there is some error in the data of Pickering et al, the detection of differences in the frequency of PCNA-positive cells in their study nonetheless raises concerns that our method might be insensitive to low levels of replication. These cell kinetic studies suggest that we reevaluate pathologists' use of the term proliferative in describing Fig 2. For example, Nobuyoshi et al²²⁵ examined 39 dilated lesions from the postmortem coronary arteries of 20 patients who had undergone angioplasty. The extent of intimal proliferation was defined by the histological appearance of stellate fibroblast-like cells with a myxomatous appearance. It is essential to note that the term proliferative as used here is a morphological term, not a measure of replication, such as thymidine index, mitotic frequency, or even the PCNA values used in our studies. Cells having this proliferative morphology are not unique to restenosis. Similar cells are commonly seen beneath the endothelium in areas of nonatherosclerotic intimal thickening as well as in primary atherosclerotic coronary artery lesions that have never been exposed to an interventional device.^{233 234} Although the myxomatous tissue seen in atherosclerotic or restenotic lesions does not appear to be actively proliferative, most observers agree that there is an increase in the amount of this tissue in restenotic versus primary lesions.^{159 227 233 234 235 236}

We do not know whether the increase in amount of proliferative tissue represents a redistribution of the components of lesions due to compression by the catheter or some reaction such as formation of extracellular matrix, migration, or cell proliferation at a low level not measured by current methods. The appearance of proliferative tissue within the wires of stented coronary arteries supports the idea that this is not simply a redistribution of preexisting plaque components. To date, however, we lack direct histochemical evidence of replication.²²⁹ Perhaps the wires push into the wall, or the wall components migrate around the wires.

	Relevance of Animal Stenosis to Human Restenosis

Top Introduction Formation of the Intima Neointimal Formation: A Generic... Pharmacology of Neointimal... Potential Clinical Targets Based... Role of Intima in... Special Properties of... Intimal Cells Overexpress... Mechanisms Controlling Plaque... Pathological Significance of... Mechanism of Lumen Occlusion... The Nature of Restenosis... Relevance of Animal Stenosis... Future Directions References

 
These data on replication force us to reconsider the relevance of animal models to the human problem. The issue is illustrated in Fig 3. Almost all animal studies, particularly those done in the rat, measure a decrease in lumen size from the initially normal situation. This can rightly be called stenosis. In contrast, the clinical problem is defined by "loss of gain," which is the extent of dilatation lost after an atherosclerotic vessel has been dilated to achieve what the interventional cardiologist believes is an optimal diameter (eg, a popular clinical definition of restenosis is >50% loss of initial luminal diameter gain). This loss of gain, rather than the preexisting vessel caliber, is rightly called restenosis. By current angiographic criteria, even a return of the human vessel to its predilation diameter would be defined as restenosis, despite no change in intimal mass.

View larger version (158K): [in this window] [in a new window]   Figure 3. Angiogram and IVUS of right coronary artery lesion treated by angioplasty. a, Tight stenosis (90%) of mid right coronary artery, proximal to origin of right ventricular branch (arrow). b, IVUS image of same lesion showing central placement of ultrasound catheter with minimal surrounding lumen. The echogenic inner layer and subjacent echolucent layer are generally interpreted to represent intima (large arrow) and media (small arrow), respectively. Therefore, this artery has a moderate plaque burden that is obstructing the lumen. c, Postangioplasty angiogram showing the artery to be widely patent with some residual haziness at the site of angioplasty (arrow). d, Postangioplasty IVUS image demonstrating that the echolucent arterial lumen (arrow) has been enlarged and that a moderate plaque burden remains, particularly from the 7 o'clock to 12 o'clock positions.

Thus, stenosis, as seen in most animal models of arterial injury, is very different from the loss of gain called restenosis. Studies that equate intimal hyperplasia with restenosis may be especially misleading. For example, luminal narrowing after injury to the rat carotid artery is more pronounced after 2 weeks (75%) than after 12 weeks (35%), implying that early stenosis may be due to smooth muscle contraction of the vessel.²⁴ Loss of lumen caliber could depend more on the extent of remodeling of the vessel wall to compensate for a change in mass than on the intimal mass itself.²⁰⁴

Using these definitions, we would consider the response of the rat carotid artery as a loss of preangioplasty caliber, ie, a true stenosis with a decrease in lumen size. To the best of our knowledge, angiographic studies in humans do not show that angioplasty produces a similar acceleration of loss of the preexisting lumen. This, of course, would be difficult to demonstrate angiographically because the initial lesion usually already has a critical stenosis. Furthermore, animal models, perhaps by design, require that all manipulated arteries become narrowed, ie, stenotic, as shown in Fig 3. There is no animal model in which 50% or any substantial percentage of manipulated arteries remains dilated beyond their initial unmanipulated caliber, yet this 50% rate (or higher) is the success rate seen when atherosclerotic human arteries are dilated with an angioplasty balloon.

Perhaps we need an animal model for successful angioplasty. Only recently have larger animal models been developed that take remodeling into account after angioplasty.^{237 238 239 240} Remodeling of blood vessels, however, has been discussed at length in the hypertensive microvasculature and in the response of larger vessels to changes in blood flow.^{208 241} Of particular interest, Langille and O'Donnell²⁴¹ showed that the initial response of a carotid artery to reduced flow is active vasospasm. After 2 weeks, however, this active process is replaced by a fixed remodeling that cannot be reversed by vasorelaxants. Finally, as already discussed above, Langille, working with Jamal et al,²⁰⁶ found no loss of lumen despite a 100% increase in wall mass due to intimal thickening. Similarly, Kakuta et al²³⁸ found that the extent of intimal change did not correlate with the loss of caliber in balloon-injured atherosclerotic rabbits. They propose that the major determinant of restenosis, again, is remodeling. Similar results have been found in the swine by Post et al.²⁴²

One possible way of addressing these issues in humans is to ask whether restenosis is the result of an increase in wall mass or the result of remodeling of the vessel wall to reestablish its preangioplasty caliber without a change in wall mass. Our ability to evaluate human vessels is changing because of the use of IVUS to image the affected wall. Previous data, based on histological and imaging studies, suggest that plaque compression, disruption with fracture, and dissection of the intima and media and stretching of the more normal portions of the media are involved in creating a bigger lumen.^{243 244 245 246 247 248 249 250} However, newer concepts are emerging. For example, Losordo et al²⁵¹ used IVUS to study 40 patients immediately before and after iliac artery angioplasty. The areas of the arterial wall, plaque, lumen, and neolumen resulting from the procedure were examined. Over 70% of the increase in luminal area immediately after angioplasty was contained within the plaque fracture (the so-called neolumen). Plaque cross-sectional area decreased by approximately one third, but total artery cross-sectional area increased only minimally (5%) with the dilatation. Thus, the major effects of angioplasty may be to redistribute the components of the wall. Conversely, loss of lumen, ie, a combination of elastic recoil and restenosis, might be due to healing of the fissure rather than formation of new mass.

Preliminary intracoronary ultrasound studies suggest that increases in plaque area with restenosis following angioplasty are actually small (eg, 5% to 7%).²⁵² The clinical significance of this small increase in plaque mass in an artery that is already severely diseased is unknown. The authors speculate that intimal hyperplasia may not be a dominant factor in the restenotic lesion and that, instead, remodeling may account for 60% of late lumen loss.²⁵³ This concept of "chronic recoil" is similar to the phenomenon of vascular remodeling or to the wound-healing model discussed above.

In summary, the available data do not demonstrate that cell proliferation is a major component of coronary restenosis. Some apparent restenosis at late times may even be the result of recoil occurring over the first few hours after angioplasty, followed by relatively minor additional changes resulting from plaque progression on wound healing. This sort of early recoil is called elastic recoil. Alternatively, restenosis could be the result of a redistribution of wall mass, analogous to wall changes described in hypertensive microvessels and to changes seen in arteries of experimental animals following angioplasty as described by Langille²⁰⁶ and Kakuta et al²³⁸ (above). If this is true, antiproliferative approaches to therapy, even with the elegant use of molecular biology to inhibit growth, may be irrelevant.^{54 142} It is intriguing to note that a recent study in the swine-stent model actually showed an increase in restenosis when an injured wall was irradiated to prevent cell proliferation.²⁵⁴ As ultrasound technology improves, it will be possible to test these hypotheses on the basis of serial measurements of changes in vessel wall mass. The kinetics of those changes may be useful in estimating the expected rate of cell replication in tissues undergoing restenosis.

	Future Directions

Top Introduction Formation of the Intima Neointimal Formation: A Generic... Pharmacology of Neointimal... Potential Clinical Targets Based... Role of Intima in... Special Properties of... Intimal Cells Overexpress... Mechanisms Controlling Plaque... Pathological Significance of... Mechanism of Lumen Occlusion... The Nature of Restenosis... Relevance of Animal Stenosis... Future Directions References

 
The central theme of the present review has been a discussion of the intima, the unique properties of intimal smooth muscle cells, and the possible role the intima may play in atherosclerosis and restenosis. Although we have been pessimistic about simplistic equations of intimal proliferation with loss of lumen in atherosclerosis or restenosis, this should not in any way diminish the obvious fact that proliferation must occur to some extent and at some time during both disease processes. This proliferation forms the intima, and the pathology of both of these clinical problems depends on the special properties of the intima. In atherosclerosis, it is the intima that accumulates fat, becomes calcified, expresses tissue factor, and ultimately breaks down, leading to occlusive vascular disease. Restenosis, of course, would not be a problem if we did not need to treat atherosclerosis. Moreover, any mechanism likely to account for restenosis is probably going to depend on new tissue formed after injury. This new tissue is important and may be the result of replication, migration, or extracellular matrix accumulation. Furthermore, this new tissue may contribute to lumen narrowing by occupying space, causing tissue contraction or geometric remodeling of the vessel wall. Even if replication contributes only a small number of cells to remodeling, it is possible that changes in phenotype associated with replication are also critical to the remodeling process.

At a basic science level, we need to know three things. First, we need to know much more about why the intima is different from the media. As we have discussed above, there are two possibilities. Intimal smooth muscle cells may belong to different lineages, just as different skeletal muscle cell phenotypes appear during differentiation of that cell type. Definitions of "lineage" are rapidly changing because of the identification of genes and 5' sequences that determine expression of cell type–specific proteins. Such determination elements have not yet been identified for smooth muscle cells. Presumably, the identification of such elements will lead to a much better definition of smooth muscle at a molecular level and, therefore, to an understanding of why intimal cells lose the usual patterns of gene expression seen by classic medial smooth muscle cells. On the basis of our data showing two distinct lineages in rat smooth muscle, we would like to imagine that similar mechanisms may eventually distinguish human intimal cells from medial smooth muscle cells.

The second basic science issue to be determined is the nature of the inflammatory process in atherosclerotic intima. Like any chronic inflammatory tissue, the intima of an atherosclerotic plaque is an extremely confusing place. Diagrams purporting to explain behavior of the intima on the basis of these mediators are of limited assistance in identifying therapeutic targets unless we can identify individual critical processes or molecules. It would be intriguing, however, to see if this complexity might not be simplified by identifying a critical inflammatory agent or eliciting antigen among the products of oxidation, lipid accumulation, necrosis, and coagulation. Such a critical molecule would offer an ideal therapeutic target to inhibit lesion progression. Oxidation products are especially interesting, given evidence that antioxidants, independent of lipid levels, can cause lesion regression or failure of progression.²⁵⁵ Apo(a) and related components of coagulation are also intriguing candidates, especially given the recent surprising observation that human Apo(a) transgenic mice develop lipid deposition and atherosclerotic lesions despite lack of evidence that this apoprotein interacts with lipid or alters serum lipids.²⁵⁶

The third basic science issue to be determined is the relevance of animal models. The failure of animal models to predict outcomes of trials with heparin, converting enzyme inhibitors, angiopeptin, and, more recently, lovastatin is disturbing.^{81 140 143 144 257} On the one hand, we could conclude that the best-studied model, the rat, is irrelevant, but many of these drugs have also appeared to work in other species. Alternatively, it seems to us that investigators in this field need to reconsider the premises underlying the design of the animal experiments. For example, the best understood part of the rat model is the first wave of medial replication. Much less is known about the chronic proliferation seen once the intima is formed, ie, the third wave. We also know virtually nothing about ways the neointima might contribute to lumen loss other than simple changes in mass. For example, to our knowledge, there are no studies of flow-dependent remodeling in the presence or absence of an intima despite the dramatic changes in lumen caliber that result from changes in flow. For that matter, we lack any mechanistic or molecular mechanisms to explain the changes in lumen size or wall mass attributed to remodeling. In that respect, concepts developed in the field of skin wound healing may prove useful, particularly the notion of granulation tissue contraction and remodeling.

Another critical issue is the lack of animal models with the typical features of advanced lesions. To our knowledge, the only animal model that consistently produces a lesion comparable to those seen in occlusive coronary artery disease is the spontaneously hyperlipidemic swine. These animals show extensive plaque necrosis, vascularization, rupture, and lumen narrowing at a very high frequency.²²⁰ Unfortunately, these animals are not generally available. More commonly, studies are performed by using animals with fatty streaks or fibrous caps, lesions usually not associated with occlusive coronary artery disease in humans.

At a clinical level, we need to know a lot more about how the intima contributes to lesions. Presumably, there are some basic properties of the intima that give rise to monoclonal lesion growth and initiate accumulation at focal sites. Could the properties of intima in specific sites explain why the branches of the renal artery are free of lesions but lesions are detected on the unbranched surfaces of the aorta? The observation that intima is needed for closure of the ductus arteriosus raises another set of questions.¹⁸ Do special properties of the ductus arteriosus intima control closure of this vessel? Does the natural closure of the ductus mirror processes also seen in pathological narrowing of atherosclerotic arteries?

Finally, theories of both atherosclerosis and restenosis simplistically assume that an increase in mass of the intima is the cause of loss of lumen caliber. We know that this is not simply true, but we lack a more comprehensive hypothesis. Terms like late loss, chronic recoil, or remodeling simply put names on poorly understood processes. Concepts of plaque enlargement by mural thrombosis or breakdown of plaque with critical fissuring offer a tantalizing prospect of molecular targets for therapy that again depend on our knowing why these events occur in the progressing plaque. One can guess where advances are likely to occur. Better, preferably noninvasive, imaging methods are needed to give us more precise definitions of the clinical problems. This, in turn, will hopefully lead to the development of better animal models. Already, IVUS is providing new insights into the composition and extent of human lesions and how they respond to various interventions (Fig 3). In turn, tissue from humans and from better animal models should help us learn how to control expression of the molecules that lead to plaque narrowing and ultimately death.

	Selected Abbreviations and Acronyms

 

cells = pup intimal cells µ cells = medial unmanipulated cells ACE = angiotensin-converting enzyme aLDL-R = acetylated low-density lipoprotein receptor Ang I, Ang II = angiotensin I and II, respectively Apo = apolipoprotein AT-1, AT-2 = Ang II receptors bFGF = basic fibroblast growth factor BMP = bone morphogenetic protein Col I(a1) = 1 procollagen I CYPIA1 = cytochrome P-450 ED = extra domain FGF = fibroblast growth factor GMCSF = granulocyte macrophage colony–stimulating factor ICAM = intercellular adhesion molecule IGF = insulin-like growth factor IL = interleukin IVUS = intravascular ultrasound L-NMMA = NG-monomethyl-L-arginine Lp = lipoprotein LPL = lipoprotein lipase MCP = monocyte chemoattractant protein MCSF = macrophage colony–stimulating factor MHC = myosin heavy chain NO = nitric oxide PCNA = proliferating cell nuclear antigen PDGF = platelet-derived growth factor SM = smooth muscle SMC = SM cell SR = sarcoplasmic reticulum TGF = transforming growth factor TNF = tumor necrosis factor VCAM = vascular cell adhesion molecule

	Acknowledgments

 
This study was supported by National Institutes of Health grants HL-42270 and HL-47151 and the Pacific Foundation for Cardiovascular Research. Drs deBlois and O'Brien were Research Fellows of the Medical Research Council of Canada. The authors are indebted to Dr Victor Koteliansky for help in assembling Table 1 and extensive discussions of intimal versus medial gene expression. Other contributors to Table 1 include Drs Michael Rosenfeld, Gene Liau, and Adriana Gittenberger-de Groot. The authors are also indebted to Dr Marino Labinaz of Duke University Medical Center for his insight in imaging coronary lesions and for providing Fig 3. We appreciate the critical comments regarding clinical implications provided by Dr Douglas Stewart of the University of Washington and are grateful to Drs John Simpson and Tomoaki Hinohara of Sequoia Hospital in Redwood City, Calif, for their critical comments and collaboration in atherectomy-based research. Drs Cecilia M. Giachelli and Mark W. Majesky have been vital collaborators in the studies in this review that were performed in Dr Schwartz's laboratory. Holly Kabinoff is deserving of special thanks for her expertise in preparing this manuscript.

Received May 13, 1994; accepted May 11, 1995.

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Top Introduction Formation of the Intima Neointimal Formation: A Generic... Pharmacology of Neointimal... Potential Clinical Targets Based... Role of Intima in... Special Properties of... Intimal Cells Overexpress... Mechanisms Controlling Plaque... Pathological Significance of... Mechanism of Lumen Occlusion... The Nature of Restenosis... Relevance of Animal Stenosis... Future Directions References

 
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