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Ann Thorac Surg 1997;63:582-591
© 1997 The Society of Thoracic Surgeons

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Current Review

Endothelial Cell Injury in Cardiovascular Surgery: The Intimal Hyperplastic Response

Division of Vascular Surgery, University of Washington, Seattle, Washington

	Abstract

Top Footnotes Abstract Introduction Wall Adaptation in the... Wall Adaptation in the... Graft Intimal Thickening Is... Incompleteness of Healing in... Therapeutic Approaches to... Conclusions Acknowledgments References

 
Arteries and veins respond to injury by a healing process that includes the development of a neointima. This response to injury is implicated as the primary cause of failure after arterial reconstruction. Because it is an integrator and transmitter of blood flow variations, inflammation, and growth stimuli, the endothelium is a potent regulator of long-term arterial wall mass changes. The contribution of the endothelium to intimal development depends on the type of arterial conduit. In arteries, the growth of the intima stops when the endothelium has regrown. In synthetic grafts, the endothelium stabilizes intimal growth. Hence, the mere presence of endothelial cells can influence intimal changes in arterial conduits. Understanding endothelial biology should help us define methods to prevent cell proliferation, extracellular matrix accumulation, intimal hyperplasia, and vessel narrowing.

	Introduction

Top Footnotes Abstract Introduction Wall Adaptation in the... Wall Adaptation in the... Graft Intimal Thickening Is... Incompleteness of Healing in... Therapeutic Approaches to... Conclusions Acknowledgments References

 
Arterial reconstructions fail because of intimal thickening, luminal narrowing, and thrombosis. The incidence of this unfavorable outcome is as high as 44% 10 years after aortocoronary bypass grafting with autologous saphenous vein [1] and 50% after coronary angioplasty [2]. Intimal thickening and luminal narrowing are also a major cause of failure after femoropopliteal revascularization with autologous saphenous vein or synthetic grafts or after transluminal angioplasty [3, 4]. Recent advances in the understanding of their biology suggest that endothelial cells play a central role in the development of intimal hyperplasia after arterial reconstruction. The purpose of this review is to summarize certain aspects of endothelial cell biology and to suggest how this knowledge might be used to improve the long-term results of cardiothoracic and vascular surgical procedures.

Because it is at the interface between the blood and the vessel wall, the endothelium is a potential regulator of arterial wall homeostasis. It secretes factors that regulate vascular tone, maintains the anticoagulated state of the blood, and expresses molecules that recruit inflammatory cells [5– 8]. Several lines of evidence support the idea that the endothelium is also involved in long-term modifications of the structure of the arterial wall [9, 10]. Endothelial cells could regulate the underlying cellular growth and regression [5, 11–1313], as they can secrete factors that affect smooth muscle cell proliferation, growth, migration, and death [13, 14]. They can also secrete enzymes, or inhibitors of these enzymes, able to degrade components of the intimal extracellular matrix. The balance of these endothelial-derived activities probably regulates vessel development.

The endothelium is present during the period of smooth muscle cell proliferation, although at times these cells proliferate with endothelium absent. During blood vessel formation in the embryo, smooth muscle cell recruitment follows the organization of endothelial cells in tubes [15]. The inhibition of endothelial formation in the embryo prevents the development of vessels [16]. The strongest evidence in support of a role for endothelium in regulating vessel wall mass comes from studies of arterial injury. These experiments are of particular importance to surgeons because all forms of vascular reconstruction involve injury.

Arterial reconstruction is associated with different types of arterial injury. One type is mechanical injury of the native vessel. It includes dissection of the artery, suture, endarterectomy, thrombectomy, and luminal angioplasty. A second type of injury is associated with the implantation of nonarterial structures such as autologous vein graft, synthetic graft, and stent in contact with the arterial blood flow. The different forms of injury induce a healing response that tends to optimize the relationship between the newly shaped arterial conduit, the surrounding tissues on the adventitial side [17], and the blood flow on the intimal side [18]. As part of the response, cells proliferate and extracellular matrix is synthesized and deposited, resulting in an intimal thickening composed of smooth muscle cells as well as collagen, elastin, and proteoglycans [19–22]. In favorable outcomes, the healing process reaches a steady state, and the luminal area is maintained in a functional range. In other instances, the intimal growth leads to obstruction of the lumen and downstream ischemia.

	Wall Adaptation in the Absence of Endothelial Cells

Top Footnotes Abstract Introduction Wall Adaptation in the... Wall Adaptation in the... Graft Intimal Thickening Is... Incompleteness of Healing in... Therapeutic Approaches to... Conclusions Acknowledgments References

 
A normal artery is readily injured by the passage of a balloon embolectomy catheter (Fig 1) [23]. In the rat carotid artery damaged in this way, the injury strips away the endothelial cells and stretches the underlying media. Immediately after injury, platelets adhere to spread over, and degranulate on the denuded vessel. Smooth muscle cells start proliferating in the media approximately 24 hours after injury: the percentage of dividing smooth muscle cells increases from a basal level of 0.06% per day to 10% to 30% per day. After 4 days, smooth muscle cells migrate into the intima, where some of them continue to proliferate to form a thickening. The deposition of extracellular matrix around the intimal cells increases the thickening of the intima [23]. By 3 months, a steady state is reached. The intima at this time is 20% cells and 80% extracellular matrix.

View larger version (12K): [in this window] [in a new window]   Fig 1. . Intimal thickening in the absence of endothelium. The injury of endothelial cells on a native vessel removes the barrier that normally prevents growth factors to reach the medial smooth muscle cells. In addition, the inhibitory activity of the endothelium on smooth muscle cell proliferation is missing. The result is smooth muscle cell migration and proliferation in the areas where the endothelium has been deleted. (bFGF = basic fibroblast growth factor; PDGF = platelet-derived growth factor.)

The initial events, smooth muscle cell proliferation in the media and migration into the intima, have been shown to be triggered by two different growth factors: basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF). It appears that these two growth factors regulate different events. Basic fibroblast growth factor is released from damaged endothelial and arterial smooth muscle cells. Its infusion stimulates the proliferation of smooth muscle cells in the media. An antibody against bFGF prevents the proliferation of smooth muscle cells in the media by 80% to 90% but has no effect on subsequent cell proliferation in the intima [26, 27].

One of the three isoforms of PDGF, PDGF-BB, stimulates the migration, but not the proliferation, of smooth muscle cells in vivo from the media into the intima and increases intimal thickening when infused after balloon-related injury [28]. In vitro, the PDGF-BB isoform induces both smooth muscle cell proliferation and migration, whereas PDGF-AA has only a proliferative effect [29]. In addition, PDGF prevents programmed cell death (apoptosis) of cultured arterial smooth muscle [30]. This could also contribute to the increase in the number of cells in the intima. Platelet -granules are a major source of PDGF [13]. Platelet-derived growth factor is also synthesized and secreted by vascular cells. A small number of cells in the neointima after balloon-caused injury express PDGF-B messenger RNA [31]. Thrombocytopenia and antibodies against PDGF both decrease intimal thickening by inhibiting smooth muscle cell migration without affecting proliferation in the balloon injury model [32, 33]. Transforming growth factor ß, angiotensin II, and bFGF may also contribute to the migration of smooth muscle cells into the intima [34–36].

The growth and migratory activities of these factors may be mediated in part by the induction of certain proteases needed by cells for movement through matrix. Two classes of proteinases, plasminogen activators and metalloproteinases, have been shown to be upregulated during the development of intimal thickening in the balloon injury model. Both tissue plasminogen activator and urokinase convert plasminogen to plasmin. After balloon-related injury, tissue plasminogen activator is expressed by migrating smooth muscle cells, whereas urokinase is expressed by proliferating smooth muscle cells [37]. In vitro, PDGF and bFGF increase tissue plasminogen activator production by smooth muscle cells [38]. In vivo, the blockade of PDGF activity results in a reduction in tissue plasminogen activator production by smooth muscle cells and in a reduction in intimal thickening [39]. An increase in metalloproteinases is also evidenced during the migration of smooth muscle cells from the media into the intima after arterial injury. Their inhibition by pharmacologic agents results in substantial inhibition of the intimal thickening [40].

The two proteolytic pathways have specific physiologic inhibitors, which are also upregulated by arterial injury in the rat (Hasenstab D, Forough R, Clowes AW; unpublished results). This supports the idea that the migration of smooth muscle cells from the media into the intima is regulated by a proteolytic-antiproteolytic balance. The endothelium under different stimulatory conditions is able to synthesize both activators and inhibitors of extracellular matrix proteolysis and thus could play a role in the homeostasis of intimal thickening by controlling the proteolytic balance [41].

In the neointima lacking endothelium, smooth muscle cells continue to proliferate [25]. Growth factors overexpressed in this region include PDGF-A, transforming growth factor ß, insulinlike growth factor 1, and the receptor to angiotensin II [34, 42–45]. Smooth muscle cells in the neointima have an increased responsiveness to transforming growth factor ß and angiotensin II [34, 46]. Some factors such as interferon secreted by T lymphocytes in the neointima may inhibit smooth muscle cell replication [47, 48]. As emphasized earlier, regenerating endothelium may inhibit intimal smooth muscle growth [25].

The mechanisms by which endothelial cells inhibit intimal thickening are unknown. Cells could form a barrier to the influx of growth factors. Endothelial cells could release inhibitors of smooth muscle cell proliferation. Endothelial cells secrete nitric oxide (NO) and heparan sulfate, both of which inhibit smooth muscle cell growth in vitro [14, 27, 49]. These factors could make the smooth muscle cells unresponsive to other stimuli. For example, recombinant bFGF administered to either the luminal or adventitial surface of deendothelialized arteries stimulates medial smooth muscle cell proliferation. However, bFGF has no effect on vessels with a normal endothelium [26].

Interest has been focused on the functional properties of the endothelium after injury. Although they grow and recover the denuded surface, endothelial cells lose their ability to synthesize endothelial-derived relaxing factor–NO after repeated mechanical injury [50]. The long-term result could be continued intimal ingrowth because the regenerated endothelium has not recovered all its functions.

	Wall Adaptation in the Presence of Endothelial Cells

Top Footnotes Abstract Introduction Wall Adaptation in the... Wall Adaptation in the... Graft Intimal Thickening Is... Incompleteness of Healing in... Therapeutic Approaches to... Conclusions Acknowledgments References

 
Healing of vein grafts involves responses to both operation-related injury [51, 52] and arterial hemodynamic conditions [22]. Vein grafts in the arterial circulation develop an intimal thickening, whereas veins transposed in the venous circulation do not, findings suggesting that hemodynamic stress is a major determinant in venous bypass structural changes [53]. Intimal thickening in vein grafts has been considered an adaptation to the hemodynamic switch from venous to arterial blood flow [54, 55]. Illustrating the hemodynamic dependence of vein graft structural changes in contact with arterial flow is the regression of these changes when vein grafts are returned to venous flow [56].

The time course of vein graft intimal thickening has been described in a rabbit model in which the external jugular vein is transplanted into the carotid artery [57]. Platelets, microthrombi, and leukocytes adhere mostly at the anastomoses, where the endothelium is denuded. By 2 weeks, the denuded surface is completely recovered with endothelial cells. At this time, intimal thickening starts to develop. It is composed of smooth muscle cells. During the first 4 weeks, the increase in wall mass is associated with smooth muscle cell proliferation and accumulation. As smooth muscle cell proliferation stops, the deposition of extracellular matrix accounts for the increase in the intimal thickening. The graft wall thickness, circumference, and cross-sectional area reach a maximum at 12 weeks [58].

During the development of intimal thickening in vein graft adaptation to arterial flow, smooth muscle cell migration and proliferation occur underneath endothelial cells. A similar pattern of growth has been described in synthetic graft healing in a primate model [18, 59]. This pattern contrasts with the healing of injured native arteries, where smooth muscle cells proliferate in the absence of endothelial cells. As platelets and thrombus are not present, smooth muscle cell growth must be stimulated by some other source of mitogens. The source of growth factors could be the vascular cells themselves. Healing prostheses covered with endothelium explanted and perfused in vitro release PDGF [60]. Cultures of intimal hyperplasia–derived smooth muscle cells express PDGF-AA and transforming growth factor ß1, two potent growth regulators of smooth muscle cells [61]. In situ hybridization performed on healing polytetrafluoroethylene (PTFE) grafts in baboons showed PDGF-A messenger ribonucleic acid expression localized in endothelial cells and in adjacent smooth muscle cells [62].

	Graft Intimal Thickening Is Regulated by Arterial Blood Flow and Pressure

Top Footnotes Abstract Introduction Wall Adaptation in the... Wall Adaptation in the... Graft Intimal Thickening Is... Incompleteness of Healing in... Therapeutic Approaches to... Conclusions Acknowledgments References

 
Intimal smooth muscle cell proliferation in vein grafts stops when the graft ratio of the radius to wall thickness matches the ratio in arteries. This result supports the idea that the intimal thickening in vein grafts is regulated by hemodynamic factors. The modulation of intimal thickening in response to tangential stress (applied transversely to the arterial wall) and shear stress (applied longitudinally to the arterial wall) has been investigated. The tangential wall stress on the vessel wall is the force that causes an increase in circumference. One component of tangential wall stress is blood pressure. In response to arterial pressure, vein grafts develop a structure able to counter this increased strain. In the rabbit vein graft model, if a rigid cuff is wrapped around the graft, part of this strain is supported by the cuff [58]. It has been shown that such a support reduces the wall thickening in chronic implantation. The intimal thickening increased by tangential stress could influence the development of atherosclerosis in vein grafts. In the hypercholesterolemic rabbit, lipid-laden macrophages accumulate in the intimal thickening [63]. The reduction in intimal thickening also reduces the intimal lipid deposition [64].

Most available synthetic grafts (eg, PTFE) are rigid, and the tangential strain is likely to be supported by the graft itself, not by the neointima. The shear stress may regulate the development of intimal thickening in this situation. The role of blood flow and shear stress in prosthetic graft healing has been studied in endothelialized vascular grafts in baboons. Complete endothelialization is achieved by 3 weeks after the implantation of porous PTFE prostheses [65, 66]. Endothelial cells come from capillary ingrowth through the 60-mm pores in the graft wall and from the cut edges of the adjacent artery [65, 67]. Underneath, smooth muscle cells proliferate, and extracellular matrix accumulates (Fig 2).

View larger version (21K): [in this window] [in a new window]   Fig 2. . Intimal thickening in the presence of endothelium. After the implantation of a porous polytetrafluoroethylene graft, microvessels arise from the adventitia and penetrate through the pores. The endothelium from these microvessels then forms a monolayer and lines the intimal side of the graft. Then smooth muscle cells accumulate in the neointima. In this situation, the endothelium and the smooth muscle cells themselves contribute to the increase in intimal mass by secreting growth factors such as platelet-derived growth factor in both an autocrine and a paracrine manner. (1 = autrocrine loop; 2 racrine loop.)

In this model, the flow switch increases the intimal thickening underneath a confluent endothelial layer. The decrease in shear stress is physiologically transduced to intimal smooth muscle cells through the endothelium. The requirement of an intact endothelium to induce long-term modifications of arterial diameter after blood flow reduction has been shown in another model [9]. An increase in shear stress leads to a regression of graft intimal thickening. In arteries, an acute increase in shear stress causes rapid arterial dilation involving endothelial-dependent vasodilatory pathways, cyclooxygenase and NO synthase [5]. In animals, both vasodilator pathways are involved, whereas in humans, the NO pathway seems to be more important than the prostaglandin pathway [70].

It has been proposed that shear stress–induced cytoskeletal reorganization serves as a transducer of the mechanical stress applied on the endothelial cells and leads to a transcriptional activation of NO synthase [12]. A chronic increase in blood flow results in an increased content of cyclic guanosine monophosphate in the arterial wall, which suggests that the NO pathway can be chronically stimulated by high flow [71]. There are different mechanisms by which an increased release of NO could induce regression of intimal thickening (Fig 3). Nitric oxide could reduce the number of cells in the intima. Nitric oxide inhibits smooth muscle cell proliferation and might induce the death of these cells [14, 27, 72]. Nitric oxide reduces the expression of adhesion molecules on the endothelial cells and the recruitment of inflammatory cells, which are a source of growth factors [73, 74]. The release of NO has no effect on endothelial cell growth [75]. Nitric oxide decreases the synthesis of collagen by smooth muscle cells and could influence the extracellular matrix mass in the intima [76].

View larger version (22K): [in this window] [in a new window]   Fig 3. . Acute and chronic increase in arterial luminal area under shear-stress stimulation of the endothelium. An increase in shear stress activates endothelial nitric oxide (NO) synthase and NO production. The acute release of NO is responsible for arterial dilation. The chronic increase in NO inhibits smooth muscle cell protein synthesis and proliferation, and possibly induces cell death. (cGMP = cyclic guanosine monophosphate.)

	Incompleteness of Healing in Venous and Synthetic Prostheses

Top Footnotes Abstract Introduction Wall Adaptation in the... Wall Adaptation in the... Graft Intimal Thickening Is... Incompleteness of Healing in... Therapeutic Approaches to... Conclusions Acknowledgments References

The cells in these grafts may not return to the resting state. Even though endothelial cells in the vein graft reach a confluent state on the intima, they continue to proliferate at a high rate [63]. In nonporous PTFE grafts, both endothelial and intimal smooth muscle cells continue to proliferate 12 months after implantation in baboons [18, 59]. The growing edges of intimal thickening are the regions where endothelial and smooth muscle cell proliferation is the most intense. Intense proliferation of both cell types also occurs at the anastomoses. As a consequence of smooth muscle cell proliferation and extracellular matrix deposition, intimal thickness at the anastomoses increases between 6 and 12 months.

The reasons for ongoing intimal proliferation in vein and synthetic grafts are not evident. It can be argued that both conduits are imperfect scaffolds for endothelial and smooth muscle cell growth, leading to a permanent biologic instability. In PTFE grafts, the internodal distance of the pores influences the development and the stability of intimal hyperplasia [67]. The instability of the anastomotic region is consistent with the clinical observation of anastomotic predilection for obstructive intimal thickening. The anastomosis is a complex transitional region where the blood flow is not laminar and the transition in terms of compliance is sudden [77]. Each of these could be a determinant of anastomotic hyperplasia.

Whatever the mechanisms are, it can be concluded that the endothelial cells present in this transitional region, even on prostheses in humans [78, 79], do not prevent the development of occlusive intimal thickening. The evidence suggests that endothelial cells in healed vein grafts do not display functional characteristics of arterial endothelium. Animal and clinical studies indicate that when the vein is handled carefully during operation, most of the venous endothelial cells remain on the intima after arterial flow is reestablished. The consequence could be that even though the thickening of the venous wall is somewhat like the arterial wall structure, venous endothelial cells fail to be an adequate blood flow transducer in arterial conditions.

For example, the luminal release of prostacyclin is decreased and the production of thromboxane A₂ is increased from arterialized vein grafts compared with arteries. These two eicosanoids have opposite effects on vascular tone and platelet aggregation. They are also important modulators of smooth muscle cell proliferation and might influence intimal growth [80]. In addition, the healed endothelium of vein grafts in rabbits and dogs does not normally produce endothelial-derived relaxing factor in response to stimulation by acetylcholine [81, 82]. Before implantation, the vasodilatory response to acetylcholine, involving the NO pathway, is reported to be lower in human saphenous veins than in internal mammary arteries [83].

In summary, the vasoactive properties of venous endothelium are shifted toward reduced vasodilation and increased vasoconstriction compared with arterial endothelium. This tendency is chronically maintained, or even increased, after long-term implantation in arterial blood flow conditions [56].

	Therapeutic Approaches to Prevent Intimal Thickening

Top Footnotes Abstract Introduction Wall Adaptation in the... Wall Adaptation in the... Graft Intimal Thickening Is... Incompleteness of Healing in... Therapeutic Approaches to... Conclusions Acknowledgments References

 
Endothelial cell seeding has been reported to reduce early events, such as platelet deposition, after arterial injury [84]. Data accumulated using the balloon injury model provide a rationale for testing seeded endothelial cells as a barrier to serum and platelet growth factors and as a source of heparan sulfate and protease inhibitors. Strategies using patients' endothelial cells harvested from the jugular vein and amplified in vitro have been described and even tested for clinical purposes [86]. Endothelial cell seeding with an 80% coverage of the intima by the seeded cells inhibits intimal thickening in dogs but not in rabbits [86].

The failure of anatomic restoration of endothelium after balloon-related injury in rabbits raises the question, What is the quantity of endothelial cells necessary to inhibit intimal thickening. Because the thickening of the intima after injury depends on early events such as proliferation and migration of medial smooth muscle cells, total and immediate coverage of the injured area might be necessary to achieve an inhibitory effect.

A second question is, What is the functional phenotype seeded endothelial cells should have to prevent intimal thickening. For convenience, most strategies use venous endothelial cells to cover injured arteries or prosthetic surfaces. Endothelial cells derived from veins have less "vasodilatory" capacity than arterial endothelial cells, with a higher angiotensin-converting enzyme activity and a lower NO synthesis in response to agonist stimuli [83]. This venous vasoactive phenotype is not modified by long-term exposure to arterial blood flow [56]. Venous endothelial cells, therefore, should be less capable of inhibiting smooth muscle cell proliferation than arterial endothelial cells. In addition, cultured endothelial cells have different phenotypes than endothelial cells in vivo [87]. The endothelial cell phenotype, including the ability to inhibit smooth muscle cell proliferation, can be influenced by external factors. In vitro data suggest that a pharmacologic preconditioning can decrease this inhibitory capability [88].

One other related issue is the behavior of endothelial cells seeded in a diseased artery. The phenotype of endothelial cells could be largely influenced by in vivo factors, an idea suggesting that endothelial dysfunction in arterial disease [89] and injury might be a consequence of the arterial condition, not a primary disease of endothelial cells. This is particularly obvious in arterial allografts where syngeneic endothelial cells covering the intima during the chronic phase of rejection are activated and are potent attractors of inflammatory cells. Systemic factors in coronary angioplasty, such as the activation status of circulating phagocytes before treatment, influence mid-term restenosis rates [90]. Local factors on a synthetic scaffold might be responsible for the relative failure of endothelial cell seeding to substantially improve patency of the prosthesis after infrainguinal reconstruction in humans [85, 91]. The hemodynamic environment may have a major impact on endothelial function. Poor runoff in the dog alters the endothelium-dependent arterial relaxation, a finding emphasizing that endothelial seeding success could be impaired by the feedback of the pathologic environment on the anatomically restored endothelium [92, 93].

A complementary approach to endothelial cell seeding could be in vitro or in vivo conditioning of the cells. The purpose would be to induce a suitable functional phenotype in the cells and to maintain it despite adverse signals from the pathologic environment resulting from low shear-stress, inflammatory stimuli, mechanical injury from a noncompliant scaffold, and inadequate extracellular matrix for cell differentiation on the prostheses. The surrounding extracellular matrix can modify the endothelial phenotype [94, 95]. In vitro preconditioning with shear stress has been used to increase endothelial cell adherence to prostheses [96]. In vivo, a single injection of vascular endothelial growth factor in a limb ischemic model improves the collateral vasodilatory response to serotonin and acetylcholine [97].

Another potent way to modify the endothelial cell phenotype is gene transfer. Replication-defective retroviruses can be used as vehicles to introduce a gene of interest into endothelial cells or smooth muscle cells in vitro [87]. The retroviral incorporation of the gene into the genome of the targeted cell results in the stable presence of the gene. A promoter can be chosen to achieve a high level of transcription, thus bypassing the problem of cell seeding density at the early stage after injury by a high level of protein synthesis. The feasibility of transfected smooth muscle cell seeding has been established in rat carotid artery after balloon-related injury [87]. Unlike endothelial cells, seeded smooth muscle cells can form multiple layers. The increase in the number of seeded cells potentially increases the quantity of inhibitory protein delivered to the injured arterial segment. Retrovirally transduced smooth muscle cells have also been seeded in vitro in the wall of porous PTFE prostheses and then implanted in the baboon as a local and systemic gene therapy model [98].

Cell seeding on arteries or prostheses takes advantage of the in vitro step to introduce the gene of interest. Other strategies have been developed to deliver the gene directly into the injured arterial wall using liposomes or adenoviruses as vectors [99–101]. To date, these approaches are limited by the low yield of gene transfer or by the transient gene expression after adenoviral or plasmid transfection. Nevertheless, endothelial cell NO synthase gene transfer with plasmids has proved to have a marked inhibitory effect on intimal thickening after balloon-caused injury in rats in a short-term study [99]. Inhibitors of the proteolytic pathways involved in medial smooth muscle cell division and migration are currently being investigated.

Endothelial function can also be replaced by drug administration [102, 103]. Endothelial cells in culture produce a heparinlike inhibitor of smooth muscle cell growth [49]. Heparin has been shown to inhibit smooth muscle cell proliferation [104] but has no effect on endothelial cell regeneration after rat carotid artery injury caused by a balloon [105]. Smooth muscle cell proliferation is inhibited by heparin by preventing progression through the G1 phase of the cell cycle [106]. Smooth muscle cell migration is also prevented by heparin [105, 107], possibly because it inhibits the induction of metalloproteinases [108, 109] and tissue-type plasminogen activator [110]. In addition to its action on the cellular component of intimal thickening, heparin modulates the intimal extracellular matrix composition, decreasing elastin and collagen and increasing proteoglycan deposition [20], by a regulatory effect at a posttranscriptional level [23], possibly by modulating proteoglycan enzymatic degradation [111]. These effects are independent of any anticoagulant activity of the fractions of heparin used.

Nevertheless, heparin in the baboon, unlike in the rat, fails to inhibit intimal hyperplasia after arterial injury [112]. This result is consistent with the failure of heparin to prevent restenosis after coronary angioplasty in humans. It also correlates with the different capability of heparin to inhibit smooth muscle cell PDGF-BB–induced migration in vitro in the rat and the baboon [112]. Signaling pathways triggered by heparin are being investigated.

	Conclusions

Top Footnotes Abstract Introduction Wall Adaptation in the... Wall Adaptation in the... Graft Intimal Thickening Is... Incompleteness of Healing in... Therapeutic Approaches to... Conclusions Acknowledgments References

 
The contribution of the endothelium to intimal thickening after arterial reconstruction depends largely on the type of injury induced by the procedure. Physiologic endothelial pathways controlling intimal thickening and regression are being identified in animal models. The endothelial cell functional phenotype necessary to inhibit smooth muscle cell migration and proliferation needs to be defined. An understanding of how endothelium regulates smooth muscle cell function and wall mass should then provide the basis for developing appropriate pharmacologic agents that could substitute for damaged endothelium and thereby modify the wound-healing process and improve patency after vascular reconstruction.

	Acknowledgments

Top Footnotes Abstract Introduction Wall Adaptation in the... Wall Adaptation in the... Graft Intimal Thickening Is... Incompleteness of Healing in... Therapeutic Approaches to... Conclusions Acknowledgments References

 
Doctor Allaire is supported by a grant from Laboratoire L. Lafon, France.

	Footnotes

Top Footnotes Abstract Introduction Wall Adaptation in the... Wall Adaptation in the... Graft Intimal Thickening Is... Incompleteness of Healing in... Therapeutic Approaches to... Conclusions Acknowledgments References

 
Address reprint requests to Dr Clowes, Division of Vascular Surgery, University of Washington, 1959 Pacific Ave NE, Box 356410, Seattle, WA 98195.

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Top Footnotes Abstract Introduction Wall Adaptation in the... Wall Adaptation in the... Graft Intimal Thickening Is... Incompleteness of Healing in... Therapeutic Approaches to... Conclusions Acknowledgments References

 

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