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Ann Thorac Surg 1997;63:885-894
© 1997 The Society of Thoracic Surgeons

Current Review

Endothelial Cell Injury in Cardiovascular Surgery: Atherosclerosis

Edward M. Boyle, Jr, MD, Sean T. Lille, MD, Eric Allaire, MD, Alexander W. Clowes, MD, Edward D. Verrier, MD

Divisions of Cardiothoracic and Vascular Surgery, University of Washington, Seattle, Washington


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Atherogenesis
 The Endothelial Cell Injury...
 Sources of Endothelial Cell...
 Conclusions
 References
 
Most of the indications for cardiovascular operation and many of its complications are in large part due to advanced atherosclerosis. The pathogenesis of atherosclerosis involves inflammatory infiltration of the vessel wall, cellular proliferation, fibrous plaque formation, and ultimately plaque rupture and occlusive thrombosis. Many of these events are linked, at least initially, to chronic injury of the vascular endothelium. Endothelial cell injury from hypertension, diabetes mellitus, hyperlipidemia, fluctuating shear stress, smoking, or transplant rejection disrupts normal endothelial cell function. This results in the loss of the constitutive protective mechanisms and an increase in inflammatory, procoagulant, vasoactive, and fibroproliferative responses to injury. These changes promote vasospasm, intimal proliferation, and thrombus formation, all of which play a significant role in the initiation, progression, and clinical manifestations of atherosclerosis. Understanding the role of the chronically injured endothelium and its interactions with circulating immune cells and the underlying smooth muscle cells may lead to novel therapeutic interventions for the prevention and treatment of atherosclerosis.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Atherogenesis
 The Endothelial Cell Injury...
 Sources of Endothelial Cell...
 Conclusions
 References
 
Complications of atherosclerosis are the most common indications for patient referral to cardiovascular surgeons. Progressive narrowing of coronary arteries supplying the myocardium places large capillary beds at risk for subsequent ischemic injury when stenotic plaques rupture and thrombose, acutely occluding the vessel. This results in a spectrum of derangements including myocardial stunning, ischemic valvular dysfunction, arrhythmias, and infarction requiring catheter-directed interventions or bypass operations to divert blood around diseased segments of artery. These procedures, although often life-saving, are not curative, because the long-term durability of angioplasty or coronary artery bypass grafting is limited by intimal hyperplasia and progressive atherosclerosis. The diffuse peripheral atherosclerosis that often accompanies coronary artery disease can lead to perioperative complications such as stroke, renal insufficiency, bowel ischemia, and more peripheral embolic events. In addition, severe atherosclerosis is often associated with hypertension, diabetes, hypercholesterolemia, and tobacco use, all of which are independent risk factors for the development of atherosclerosis as well as complications after cardiovascular operations.

Progress in the field of vascular biology has generated important insights into the growth factor and cytokine networks involved in maintaining the normal vasculature and in the pathogenesis of coronary artery disease. The cells of the vessel wall produce and respond to a vast array of biochemical signals that control cell replication and differentiation. The relationship between the endothelial cells, the underlying smooth muscle cells, and the cellular and serum elements of the circulating blood has emerged as the central feature in the initiation and promotion of atherosclerotic lesions. In the previous reviews, the acute consequences of endothelial cell injury have been discussed. This review is intended as an overview of the consequences of chronic endothelial cell injury for the cardiovascular surgery patient.


   Atherogenesis
Top
 Footnotes
 Abstract
 Introduction
 Atherogenesis
The Endothelial Cell Injury...
 Sources of Endothelial Cell...
 Conclusions
 References
 
Gross and histologic changes of atherosclerosis in the arterial wall can be found even in infancy. The natural history of atherosclerosis can be classified into certain categories. In the past, gross lesions were categorized as fatty streaks, which occur early in the disease process, and fibrous plaques, which are often found shortly before atherosclerotic lesions become symptomatic. Pathologists have strived to progress beyond these definitions, especially in the intermediate range, to more specific categories based on detailed histologic analysis. The Pathologic Determinants of Atherosclerosis in Youth group studied specific designated sites in arteries from more than 2,000 cases. This study led to a clear appreciation of the role of fatty infiltration in early lesions in disease-prone segments, such as the left anterior coronary artery [1]. Stary and colleagues examined autopsy specimens from 691 subjects between birth and age 39 years and developed a histologic classification of early and advanced atherosclerotic lesions (Fig 1Go). Early lesions, classified as types I, II, and III are characterized by small lipid deposits that do not disrupt the normal structure of the intima or deform the artery [2]. They are always clinically silent. Type II lesions are further subdivided into progression-prone and progression-resistant lesions. Progression-prone type II lesions appear to be co-localized with areas of adaptive intimal thickening, where lipid seems to accumulate more readily [2]. Type III and IV lesions are commonly known as preatheromatous lesions and atheromas [3]. These lesions are the histologic bridge between minimal and advanced lesions. Type III and IV lesions tend to be found at locations of previous progression-prone type II sites [2]. In type IV lesions there is a dense accumulation of extracellular lipid in addition to the lipid accumulated in foam cells. Histologically, atherosclerotic lesions are considered advanced when the structure of the intima becomes disorganized and changes in the outer or inner contour of the arterial segment are present. Stary classified advanced atherosclotic lesions as types V, VI, VII, and VIII. These lesions develop as the plaque becomes calcific and fibrotic. In late stages, surface defects develop that lead to subacute or acute thrombosis and arterial occlusion. Morbidity and mortality from coronary artery disease arise largely from these advanced lesions when thrombotic deposits increase lesional thickness or when the plaques rupture, resulting in acute thrombosis and myocardial infarction [4]. The question as to why atherosclerotic plaques, after years of indolent growth, suddenly give rise to life-threatening luminal thrombosis has led to further investigations into the biology of plaque rupture and thrombosis [4].



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  		Fig 1. . Flow diagram indicating evolution and progression of atherosclerotic lesions. Roman numerals indicate histologic types of lesions. The loop between V and VI illustrates how lesions increase in thickness when thrombotic deposits form on their surface. (Reproduced with permission from Stary HC, Chandler AB, Dinsmore RE, et al. A definition of advanced types of atherosclerotic lesions and histological classification of atherosclerosis: a report from the committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Arterioscler Thromb Vasc Biol 1995;15:1512–31, © 1995 American Heart Association.)

 
Advances in vascular biology have allowed investigators to progress beyond gross descriptions of lesions to a detailed cellular and molecular analysis of the mediators involved in the pathogenesis of atherosclerosis [5]. These advances have led to the increased appreciation of the impact of the various cellular elements in the blood, namely, macrophages, platelets, and lymphocytes, all of which are capable of adhering to the injured endothelium and subendothelial elements and releasing substances that ultimately affect lumenal size (Fig 2Go). Although the cellular elements interact in specific patterns to form the atherosclerotic lesion, the special features of these cells are considered separately below.



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  		Fig 2. . Growth factors released by vascular and circulating cells influence cellular migration and proliferation (platelet-derived growth factor {alpha} and ß [ PDGF], basic fibroblast growth factor [bFGF], heparin-binding epidermal growth factor [HB-EGF], transforming growth factor ß [TFG ß], vascular endothelial cell growth factor [VEGF], epidermal growth factor [EGF], insulin-like growth factor [IGF]). Cytokines and immune stimulatory factors promote cellular adhesion, coagulation, and lymphocyte recruitment to the atherosclerotic lesion (monocyte colony-stimulating factors [MCP-1], monocyte chemoattractant protein-1 [MCP-1], tumor necrosis factor [TNF], interleukin 1 [IL-1], interleukin 2 [IL-2], interleukin-6 [IL-6], interleukin-8 [IL-8], leukemia-inhibitory factor [LIF], granulocyte-monocyte-colony stimulating factor [GM-CSF]). Enzymes, procoagulant proteins, and other molecules elaborated by monocytes, lymphocytes, platelets, endothelial cells, and smooth muscle cells promote coagulation, alterations in vasomotor tone, and connective tissue degradation that facilitates cellular migration and plaque disruption (plasminogen activator inhibitor-1 [PAI-1], matrix metalloproteinase 1 and 3 [MMP 1 and 3], von Willebrand factor [vWF], nitric oxide [NO], adenosine diphosphate [ADP], prostacyclin [PGI2], tissue plasminogen activator [t-PA], platelet-activating factor [PAF], urokinase-plasminogen activator [u-PA]).

 
Monocytes and Macrophages
Monocytes are important in all stages of the developing atherosclerotic lesion [6]. They are particularly prominent in the early stages of atherogeneis. Experimental studies have shown that within days of initiation of a high-fat, cholesterol-containing diet, circulating monocytes are attracted to the arterial wall by chemotractants and adhesion molecules on the surface of activated endothelial cells [6]. Tumor necrosis factor (TNF) and interleukin-1 (IL-1) released by adherent, activated monocytes activate the local endothelium to express adherence molecules such as vascular cell adhesion molecule-1 and intracellular adhesion molecule-1, which attract more macrophages in a positive feedback loop [7, 8]. These adhesion molecules serve to recruit more mononuclear cells which, in turn, activate adjacent endothelial cells through the secretion of growth factors and cytokines in a paracrine fashion. Once they adhere, monocytes migrate into the subendothelial spaces and transform into macrophages [9]. The specific mediators responsible for directing transmigration in vivo are unknown, but may include fragments of tissue matrix proteins, locally oxidized lipids, and cytokines such as monocyte chemoattractant protein-1 (MCP-1) and macrophage-colony stimulating factor (M-CSF) [10]. Tumor necrosis factor and IL-1 may regulate the production of MCP-1, a potential stimulant for monocytes to migrate into the intima, along with M-CSF [10]. These powerful macrophage chemoattractant and activation factors are secreted by endothelial and smooth muscle cells in culture and possibly human atheroma specimens [11–13]. Once they have entered the vessel wall, monocytes become macrophages and scavenge oxidized lipoproteins.

Once engorged with lipid, the macrophages are referred to as foam cells, the characteristic infiltrating cells in the early atherosclerotic lesion. Studies using human monocytes in culture demonstrate that M-CSF induces scavenger receptor gene expression on macrophages that mediate the binding and uptake of modified lipoproteins, resulting in foam cell formation and lipid accumulation [11, 14]. Foam cells likely play an important role in the attraction of smooth muscle cells to the intima. Macrophages in culture release a variety of cytokines and growth factors, including both forms of platelet-derived growth factors (PDGF), transforming growth factors beta and alpha (TGF-ß and {alpha}), and basic fibroblast growth factor [15–17]. These growth factors are powerful smooth muscle cell mitogens resulting in smooth muscle cell migration and proliferation. Macrophage-derived cytokines such as TNF and IL-1 have been shown to stimulate endothelial and smooth muscle cells to produce PDGF and thereby indirectly influence the rate of lesion progression [18, 19]. Thus not only can cytokines released from macrophages and the vessel cell wall regulate the genes that encode for other cytokines, but they also serve as important regulators of the growth factors that stimulate smooth muscle cells to proliferate and secrete extracellular matrix.

In late lesions, as in all stages of the disease, macrophage transendothelial migration is facilitated by matrix metalloproteinases such as interstitial collagenase (matrix metalloproteinase-1) and stromelysin (matrix metalloproteinase-3) [20]. These proteases released by activated macrophages may contribute to the disruption of complicated plaques leading to acute thrombosis, myocardial infarction, and in many cases death [21].

T Lymphocytes
Histologically T lymphocytes are an important component of the atherosclerotic plaque. The presence of large numbers of T lymphocytes in all phases of atherogenesis suggests that there is an immune response that is directed by specific antigens [9]. These antigens, however, have not been fully characterized. Autoantibodies to oxidized low-density lipoproteins (LDLs) are common in humans, and their titers appear to correlate with the progression of atherosclerosis. This suggests that antigens derived from oxidized LDLs are presented to B and T lymphocytes during lesion development [22]. T cells include both the helper (CD+4) and killer (CD+8) phenotypes, which may be capable of clonal proliferation in response to the appropriate antigens [23]. This is especially true in transplant-associated atherosclerosis, a particularly virulent type of accelerated atherosclerosis [24]. T cells adhere to the plaque and become activated, releasing powerful cytokines that result in macrophage activation, B-cell activation, neutrophil adhesion molecule expression, and activation of cytotoxic T cells. Cytokines formed by activated T cells, such as interferon gamma, may play a role in lesion progression or regression through their effects on macrophage or smooth muscle cell activation [25].

Platelets
In the early stages of atherosclerosis there is little or no endothelial cell–platelet adhesion. In response to endothelial activation or denudation, layers of platelets begin to develop [26]. Once adherent to the vessel wall, platelets release molecules that affect coagulation, vasomotor tone, cellular proliferation, and migration of medial smooth muscle cells into the intima of the vessel wall. The importance of platelet interactions is demonstrated by several studies that have shown that animals made thrombocytopenic have significantly reduced proliferative atherosclerotic lesions compared with the extensive lesions in control animals [27]. Animals with a defect in von Willebrand factor synthesis have minimal lesions when fed a high-cholesterol diet compared with animals with von Willebrand factor [28]. These studies suggest that atherosclerotic enhancing factors released by activated, adherent platelets are critical in the development of the atherosclerotic lesion. Of the growth factors released by platelets, the most important in atherogenesis is PDGF. In addition, platelets release TFG-ß, epidermal growth factor, insulin-like growth factor-1, thrombospondin, thromboxane A2, P-selectin, serotonin, adenosine diphosphate, and histamine. These substances contribute to platelet aggregation, thrombosis, vasoconstriction, and mononuclear chemotaxis, events that are important in the acceleration of atherosclerosis. In addition to the role that platelets play in the progression of the disease, they are critical in the development of the acute obstructive thrombosis that occurs in late stages of atheroscleosis when unstable plaques rupture.

Smooth Muscle Cells
Although the cellular elements of the blood are important in propagating the atherosclerotic lesion, vascular smooth muscle cells also play a major role in the progressive encroachment of the lesion into the vessel lumen [29]. There are more than 20 growth factors that smooth muscle cells can respond to via specific surface receptors [30]. These factors, which can originate in monocytes, lymphocytes, platelets, or endothelial cells, or smooth muscle cells themselves, have both autocrine and paracrine functions that serve to change the phenotype of smooth muscle cells to promote cellular replication and secretion of large amounts of connective tissue matrix [30]. The most widely studied growth factors include PDGF, fibroblast growth factor, insulin-like growth factor, M-CSF, TGF-ß, and heparin-binding epidermal growth factor-like growth factor [31]. In addition to responding to mitogenic stimuli, smooth muscle cells can also respond to vasoactive substances such as endothelin, catecholamines, angiotensin II, prostaglandin E2, prostaglandin I2, neuropeptides, nitric oxide, and leukotrienes that promote changes in vascular tone [9]. Normally smooth muscle cells lay down extracellular matrix that forms the backbone of the vessel. Extracellular matrix is a reinforced composite of collagen and elastic fibers embedded in a viscoelastic gel consisting of proteoglycans, hyaluronan, glycoproteins, and water [32]. In the advanced stages of atherogenesis, smooth muscle cells lay down an overabundance of matrix proteins, which contribute significantly to the bulk of the lesion [32]. The combination of increasing extracellular matrix, smooth muscle cell proliferation, and increased vasomotor tone contributes to the lumenal narrowing that is characteristic of progressive atherosclerosis.


   The Endothelial Cell Injury Hypothesis
Top
 Footnotes
 Abstract
 Introduction
 Atherogenesis
 The Endothelial Cell Injury...
Sources of Endothelial Cell...
 Conclusions
 References
 
One of the most important discoveries in the field of vascular biology has been the observation that endothelial cell injury, in some form or another, is responsible for the localization of the cellular elements that drive the development of atherosclerosis. In 1973, Ross and Glomset [31] proposed the theory that atherosclerosis resulted from arterial responses to chronic injury. Ross and others subsequently showed that changes in injured endothelium lead to a disruption of its permeability characteristics, thus permitting the interaction between elements of the blood and the arterial wall. After most forms of endothelial cell injury, biochemical signals within the endothelium downregulate protective mechanisms and upregulate the synthesis of proteins that recruit platelets, monocytes, and lymphocytes, resulting in the excessive inflammatory and fibroproliferative responses. This occurs in response to chronic episodes of repeated injury or long-standing exposure to toxins such as those found in tobacco or oxidized lipoproteins. Inevitably, it is the long-term ability of the endothelium to regenerate and restore endothelial integrity that appears to be the critical determinant in the initiation and, in some cases, progression of the atherosclerosis.


   Sources of Endothelial Cell Injury
Top
 Footnotes
 Abstract
 Introduction
 Atherogenesis
 The Endothelial Cell Injury...
 Sources of Endothelial Cell...
Conclusions
 References
 
Most patients referred for cardiovascular operation have several reasons for chronic endothelial cell injury. Common causes of endothelial cell injury include biochemical and mechanical forces associated with hypertension, abnormally glycated proteins associated with diabetes, exposure to oxidized lipoproteins in hypercholesterolemia, and exogenous toxins encountered in tobacco use. Physical endothelial injury, in the form of shear forces and turbulent blood flow, may also stimulate a fibroproliferative response, which can lead to the progression of atherosclerosis. Chronic transplant rejection is associated with widespread endothelial cell insult that leads to an accelerated form of diffuse atherosclerosis. Because of the importance of these forms of injury, they are best considered separately, recognizing, of course, that in the cardiovascular surgical patient they often occur together.

Hypertension
Endothelial cell injury and subsequent dysfunction contribute significantly to essential hypertension. This is evident in both morphologic and functional changes in the endothelium noted in hypertensive patients [33]. Endothelial cells in hypertensive subjects show an increased volume and appear to have a greater degree of extrusion into the lumen [34]. Gross vessel wall modifications secondary to hypertension include enhanced smooth muscle proliferation with intimal wall thickening and proteoglycan accumulation [35]. Hypertensive patients seem to have impaired production of endothelium-derived relaxant factors and increased activity of endothelium-derived contractile substances [36, 37]. For example, patients with essential hypertension display decreased vascular response to acetylcholine, an endothelial responsive relaxant, but normal response to sodium nitroprusside, a direct smooth muscle dilator [36]. The production of nitric oxide is blunted in both animal models and humans with essential hypertension, perhaps owing to endothelial damage or enhanced elaboration of oxygen-derived free radicals, released from adherent neutrophils and monocytes, which rapidly inactivate nitric oxide before it can prevent spasm and platelet adhesion [38]. In general, vasoconstrictors tend to promote the growth of vascular smooth muscle cells whereas vasodilators tend to inhibit them, which may explain why there is enhanced fibroproliferation in patients with hypertension [37]. For example, endothelin, the most potent naturally occurring vasoconstrictive agent known, arises from the activated endothelium. There is speculation that this agent plays a role in essential hypertension as well acting directly as a smooth muscle mitogen [39]. This may lead to enhanced growth and vasoconstriction of vascular smooth muscles, which play a role in the development of atherosclerosis by increasing vessel wall mass and increasing the shear response [39]. Therefore, hypertension may not only result in part from endothelial cell dysfunction, it may also perpetuate the cycle of endothelial cell injury that contributes to the progression of atherosclerosis over time.

Diabetes Mellitus
Endothelial cell function is markedly altered in diabetes mellitus, another source of chronic endothelial cell injury. Diabetes may contribute to smooth muscle proliferation and extracellular matrix production by a variety of mechanisms. High levels of glucose can impair endothelial cell replication and accelerate cell death of endothelial cells in culture, which is associated with atherogenesis in some in vivo models [40]. It may be that when endothelial cells die and are not replaced, the underlying smooth muscle cells lose their usual inhibitory influences and proliferate. Hyperinsulinemia (in non–insulin-dependent diabetics) alters vascular structure through mitogenic effects on the underlying smooth muscle cells. High concentrations of glucose enhance the formation of extracellular matrix by endothelial cells, which leads to thickened basement membranes [39]. Diabetics have increased levels of von Willebrand factor and decreased levels of tissue plasminogen activator, both of which lead to a hypercoagulable state [39]. This results in an enhanced adhesion of platelets, which carry potent growth factors that enhance the progression of atherosclerosis. Hyperglycemia leads to an impaired endothelium-dependent relaxation, which is supported by the observation that endothelin and angiotensin II levels are elevated in diabetics. Resulting complications include accelerated atherosclerosis, diabetic nephropathy, and hypertension, all of which increase the risks of cardiovascular operations.

Endothelial Lipid Metabolism
For many years the association between chronically elevated levels of plasma lipoproteins, particularly LDLs and very-low-density lipoproteins, and atherogenesis has been appreciated. Recently, the role of the injured endothelium in this process has become increasingly understood. When a diet rich in fat is ingested, cholesterol is generated and processed in the liver. Although there are wide variations in the ability of the body to metabolize cholesterol, the resulting LDL is taken up in part by the endothelium, where it is transformed into its oxidized form. This oxidized form of LDL has been shown in cultured endothelial cells to promote the enhancement of adhesiveness for monocytes, as well as the increased production of MCP-1 [41]. In early lesions, monocytes, responding to chemotactic stimuli and binding to specific endothelial cell adhesion molecules (such as vascular cell adhesion molecule), begin to adhere to the surface of the overlying endothelium [9]. Monocytes subsequently migrate into the subendothelium, proliferate, and differentiate into macrophages. Scavenging macrophages take up the oxidized LDL, resulting in the formation of lipid-laden foam cells, which, combined with the proliferating smooth muscle cells, make up the bulk of the fatty streak [9]. These macrophages release cytokines, such as IL-1, TNF, and interleukin-8, that cause the endothelium to express adherence molecules, resulting in further amplification of cytokine-mediated endothelial cell injury and subsequent exposure of the underlying smooth muscle cells. These cells, which have been activated by factors released by the macrophages, manufacture and express tissue factor. Tissue factor, found on activated monocytes, on endothelial cells, and in the subendothelial tissues, is a vital component in the initiation of coagulation through thrombin generation and platelet activation and adherence [42–44]. Thrombin is also a powerful smooth muscle mitogen. The activated, adherent platelets release potent growth factors that further stimulate the proliferation of smooth muscle cells and macrophages. Furthermore, oxidized LDL inhibits endothelium-dependent relaxation factors and promotes endothelium-dependent as well as endothelium-independent contractions. These consequences result in alterations in vascular tone leading to vasospasm and thrombus formation, both of which are common events in patients with severe coronary atherosclerosis [45].

Smoking-Related Arteriopathy
Cigarette smoking is known to increase the incidence of heart disease many-fold. Furthermore, smoking cessation has been associated with a decline in cardiovascular deaths [46]. Autopsy studies demonstrate an increased prevalence of atherosclerotic lesions in coronary arteries from cigarette smokers, with the amount of tobacco consumed directly correlating with the severity of the disease [47]. These epidemologic associations provide a basis for the hypothesis that smoking is associated with the pathogenic mechanisms that accelerate the development of atherosclerosis. The exact role that smoking plays in mediating these effects, however, is not clearly understood. Inhaled cigarette smoke contains more than 4,865 substances, any number of which may be toxic [48]. It has been suggested that cigarette smoke contains mutagens that induce the transformation of smooth muscle cells to a proliferative state [48]. Nicotine, however, has received the most attention and is postulated to be the important component of smoking responsible for the deleterious effects on the cardiovascular system [49]. Long-term nicotine administration in animals produces morphologic changes in the endothelium [50–52]. These alterations include endothelial cell swelling, subendothelial edema, increased formation of surface projections, and widening of endothelial junctions. Chronic nicotine exposure is associated with an increased frequency of endothelial cell death and decreased rate of endothelial cell mitosis [53]. As a result of the diminished endothelial cell turnover, the endothelium may be unable to regenerate a surface at sites of injury. Leaky junctions around dead endothelial cells may allow the transport of macromolecules such as oxidized LDLs, resulting in increased macrophage activation and foam cell formation. Smoking also appears to be associated with an increase in fibrinogen levels, which is in itself an important risk factor for myocardial infarctions and stroke [54]. In addition to its injurious effects on the endothelium, smoking has also been shown to disrupt the vasomotor regulation of the vessel wall through the inhibition of nitric oxide production [55]. Nitric oxide is also an important inhibitory factor of smooth muscle cell proliferation and platelet and macrophage adhesion.

Shear-Related Endothelial Cell Injury
Blood pressure in the arterial range appears to be essential for the development of atherosclerosis. This is suggested by the observation that atherosclerosis does not develop in veins, but rapidly develops in arterialized veins, such as saphenous vein bypass grafts [56]. The localization of severe atherosclerotic lesions at branch points and at bends in the vascular tree suggests a role for hemodynamic forces in the development of atherosclerosis. Mechanical stresses at or just beyond vessel branch sites are important stimuli that interact with other endogenous and exogenous factors to regulate endothelial and smooth muscle cell behavior [57]. As reviewed by Gotlieb and Langille [57], forces imposed on the vascular wall are of three types: pressure, tension (stretch), and shear. Pressure represents a force acting inward everywhere on the surface of tissue elements. Pressure is exerted at the intimal layer and equals intravascular blood pressure. Tension pulls tissue along one axis, normally without constraining the tissue in the other direction. Shear exerts forces in opposite directions on opposite faces of tissue elements. High, low, and fluctuating shear forces appear to be involved in the development of atherosclerotic lesions. The importance of low shear stress in the development of vascular disease is revealed by experimental findings showing that areas of low stress in the vascular system, such as the carotid sinus, have an increased predisposition for atherosclerotic development [58]. This may allow prolonged residence times for cells to adhere and decreased production of nitric oxide and prostacyclin [56]. In these areas it is postulated that eddy currents develop that activate the endothelium to recruit monocytes and lymphocytes, which initiate atherogenesis [56]. In contrast, disruption of the endothelium by high shear forces may be particularly marked at areas such as branches and bifurcations, where advanced proliferative lesions are often found. These areas often contains the least amount of lipid, suggesting an alternative mechanism of lesional development [58]. The capacity of the endothelium to regenerate after recurrent injury appears to be impaired at these areas [9]. Chronically exposed subendothelial elements allow the adhesion of monocytes, lymphocytes, and platelets, all of which work together to enhance fibroproliferation. Although the role of high or low shear stress as an inciting factor in the development of atherosclerosis is controversial, what is clear is that at many sites where advanced lesions are predictably found, there are marked abnormalities in flow with wide, complex fluctuations in the degree of shear stress.

How mechanical forces result in cellular activation is becoming increasingly understood. Endothelial cells are uniquely situated to respond to hemodynamic forces, making the vascular endothelium the primary transducer of hemodynamically imposed mechanical events [59, 60]. When endothelial cells sense different flow environments, there are marked changes in cell signaling, stimulating the secretion of factors that regulate vessel tone such as nitric oxide, prostacyclin, and endothelin-1 [61–63]. Moreover, endothelial cells possess the ability to promote long-term alterations in endothelial properties through the induction of specific genes that encode new proteins [64, 65]. Resnick and colleagues [66] demonstrated a shear stress response element located in the transcriptional regulatory regions of human PDGF-ß gene. In addition, this selective pattern of regulation was also noted for the adhesion molecule–intracellular adhesion molecule-1 gene, which was shown to contain the shear stress response element within its core promoter sequence [67]. The consensus DNA sequence of this response element (GAGACC) is also present in other genes that are responsive to shear stress, such as tissue plasminogen activator, TFG-ß, and endothelin-1 [57]. There is currently a dedicated body of literature growing that details the shear response of various genes involved in cell growth and inflammation.

Transplant Arteriopathy
Cardiac transplantation is currently the mainstay of treatment for severe, end-stage heart failure. The long-term function of the transplanted heart is limited by the development of an accelerated form of atherosclerosis. This form of atherosclerosis is present in virtually all transplanted hearts by 1 year after transplantation [24, 68]. Because the entire coronary tree is involved, retransplantation is usually the only therapeutic alternative [69]. Similar pathologic changes are observed in cadaveric arterial allografts used as an alternative to autologous vein grafts [68, 70]. Although there are many instructive clinical observations that have led to an improved understanding of this disease, the vascular biology is poorly understood. Experimental observations have led to speculations that the possible etiologic mechanisms may include immune, infectious, and ischemia-reperfusion–induced vascular injury [71].

A concentric intimal thickening together with medial injury and adventitial inflammation are features of chronic arterial allograft rejection. The intimal thickening in allograft rejection may be a response of the arterial wall to an immune injury, possibly increased by nonimmune factors. It is clear that allograft transplantation-associated arteriosclerosis is determined by graft alloimmunogenicity, because isografts display no pathologic changes in the three layers. Arterial wall immunogenicity is attributable to the arterial wall cells. The arterial extracellular matrix alone is not able to induce allograft rejection [72]. Histoincompatibility across minor tissue antigens with no major histocompatibility complex mismatch is able to induce a coronary transplantation-associated arteriosclerosis in a cardiac allograft model in the rat with no immunosuppressive treatment [73].

The roles played by endothelial and smooth muscle cells as critical targets of chronic arterial rejection are unclear [74]. Early after engraftment, endothelial cells are directly exposed to the recipient immune system because of their luminal and adventitial location. Both endothelial and smooth muscle cells express functional major histocompatibility complex class II antigens, but smooth muscle cells are less potent stimulators of lymphoproliferation in vitro than endothelial cells [75, 76]. For these reasons graft endothelial cells are better candidates than medial smooth muscle cells to trigger the early phase of the immune response that leads to accelerated atherosclerosis. During the acute phase of arterial rejection, endothelial cells allow the attachment and recruitment of monocyte-macrophages and T lymphocytes on the graft [77]. The sequential studies of untreated arterial allograft rejection in the rat aortic graft model show that many endothelial cells are swept away by the acute phase of the rejection, whereas smooth muscle cells are present during the chronic phase of the rejection characterized by the intimal thickening [78]. Smooth muscle cells positive for anti–alpha-actin, desmin, and vimentin staining accumulate in the intima as smooth muscle cells disappear in the media. This suggests a migration of medial smooth muscle cells into the intima at the early stage of intimal thickening. It has been shown that smooth muscle cells express TNF, TGF-ß and PDGF-A chain, PDGF-BB, and IGF-1 receptors, factors that contribute to smooth muscle cell migration and proliferation, and to extracellular matrix synthesis in the intima [79]. Monocytes and macrophages are a potent source for these growth factors. These cells are found in the intimal thickening underneath the endothelial cells of host origin after the third week after engraftment in the rat model. It has been proposed that the intimal thickening in arterial allograft rejection is a delayed response to the immune injury of graft medial smooth muscle cells [78].

The fact that endothelial cells of graft origin are swept away during the acute phase of rejection before the development of intimal thickening does not imply that the endothelium per se plays no role in the chronic intimal response. In chronically rejected vascularized allografts under immunosuppressive treatment, endothelial cells from the graft are likely to be present. In human cardiac allograft recipients, transplantation-associated arteriosclerosis has been associated with a cell-mediated alloreactivity against the graft's endothelium [80]. In the rat arterial transplant model, endothelial cells are of host origin by 3 weeks after engraftment. These endothelial cells are highly activated and express major histocompatibility complex class II antigens [78, 81]. They also express the JE antigen, a murine equivalent of MCP-1, which is a chemoattractant for monocyte-macrophages [73]. Syngeneic endothelial cells are probably activated by the surrounding environment and contribute in return to the inflammatory phenotype of the intimal thickening. This suggests that the phenotype of the endothelial cells can be modified by their environment in the allograft rejection context and contribute to the chronic phase of rejection without being antigenic.


   Conclusions
Top
 Footnotes
 Abstract
 Introduction
 Atherogenesis
 The Endothelial Cell Injury...
 Sources of Endothelial Cell...
 Conclusions
References
 
The number of growth factors, cytokines, and chemokines that affect atherogenesis are enormous. The temporal and spatial distribution of these agents suggests that therapy targeted to any single factor is unlikely to be as successful as therapies directed at common mediators and downstream effectors [30]. At the basic science level, new insights are being gained into how these mediators and growth factors work together to orchestrate the development of atherosclerotic lesions. The information from these studies may potentially lead to the development of new therapies, using recombinant cytokines, soluble receptors, antibodies, or the transfection of specific genes at vascular sites prone to lesion formation, that could affect the way we treat patients with end-stage cardiovascular disease. Until then, efforts to prevent endothelial injury by medically managing hypertension, diabetes, and hypercholesterolemia and the avoidance of aggravating factors such as tobacco will prove to be the most successful means of preventing many of the devastating complications of atherosclerosis.


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Atherogenesis
 The Endothelial Cell Injury...
 Sources of Endothelial Cell...
 Conclusions
 References
 
Address reprint requests to Dr Verrier, Department of Surgery, University of Washington, 1959 Pacific Ave NE, Box 356310, Seattle, WA 98195 (e-mail: verriere{at}ctd.surgery.washington.edu).

Recent discoveries in the field of vascular biology have led to an expanded understanding of the pathogenesis of many of the immediate and long-term complications of patients undergoing cardiovascular operations and interventional cardiologic procedures. In particular, the vascular endothelium has emerged as the central focus of many of the biologic events that affect the preoperative, operative, and postoperative course of nearly all heart surgery patients. A recurring theme in the study of endothelial cell biology is the crucial role that endothelial cell injury plays in the difficulties that our patients encounter. The deleterious effects of endothelial cell injury are most evident in the acute syndromes of vasospasms, coagulopathy, ischemia/reperfusion injury, and the systemic inflammatory response to cardiopulmonary bypass. In addition, chronic endothelial cell injury contributes to the development of anastomotic narrowing and the progression of atherosclerosis, both of which limit the long-term success of coronary artery bypass grafting. Because of the increasingly recognized role of the endothelium in cardiovascular function there is a tremendous amount of basic science information detailing the response of the endothelium to injury. This is the last in a series of seven reviews intended as an introduction to the major topics of endothelial cell biology that are of importance to the practicing cardiothoracic surgeon. In particular, the authors have focused on the role that the endothelium has on the development of vasomotor dysfunction, bleeding and thrombosis, neutrophil-endothelial cell interaction, and obstructive arteriopathy. The aim of these reviews is to provide a concise reference point for cardiothoracic surgeons as they evaluate the ever-accumulating research findings and new therapies that stem from the study of the endothelium in response to the insults encountered in cardiothoracic surgery.

Edward D. Verrier, MD


   References
Top
 Footnotes
 Abstract
 Introduction
 Atherogenesis
 The Endothelial Cell Injury...
 Sources of Endothelial Cell...
 Conclusions
 References
 

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