Endothelial Dysfunction And Vascular Smooth Muscle Abnormalities

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In general, the normal endothelium is in an inhibitory mode-inhibiting contraction, thrombosis, white cell adhesion, and vascular smooth muscle growth (Q-hB; Figs. 6-4 and 6-5). Endothelial dysfunction is one of the important concepts that has developed in vascular biology over the last decade. Implicit in the term is the recognition that the fundamental or normal functions of the endothelium are not fixed, but are mutable. Thus, the endothelium in a given area may lose its vasodilator predominance, become prothrombotic or less thrombolytic, begin to support leukocyte adherence (which may be a normal response in the inflammatory process), or stimulate rather than inhibit smooth muscle migration and proliferation. It is likely that endothelial dysfunction accounts ultimately for a large portion of cardiovascular diseases.

Oxidative Stress and Vascular Disease

In the past several years, it has become clear that vascular cells, including endothelial, vascular smooth muscle, and adventitial cells, can produce reactive oxygen species (ROS). These include superoxide anion, hydrogen peroxide, NO, and peroxynitrite. In numerous pathophysiologic conditions, the production of ROS in the vascular wall is increased, resulting in a situation commonly referred to as oxidant or oxidative stress. Several enzyme systems have been implicated in production of ROS.

Recent studies suggest that an NADH/NADPH-driven oxidase is a major source of ROS in endothelial and vascular smooth muscle cells. This oxidase is a multisubunit enzyme that has only partial similarity to the neutrophil respiratory burst oxidase. For example, in VSMCs, the subunit p22phox has been shown to be critical for its function, whereas the gp91phox subunit appears to be absent.!3! In endothelial cells, the existence of all of the neutrophil subunits has been demonstrated, although it is not clear that they function together to produce ROS as they do in the neutrophil.132 The adventitia also contains fibroblasts and macrophages that express multiple oxidase subunits.133 Importantly, the NADH/NADPH vascular oxidase is activated by several pathophysiologic stimuli, including angiotensin II, mechanical stretch, cytokines, and thrombin.134-137

A second source of ROS is eNOS. As discussed previously, in the absence of tetrahydrobiopterin or L-arginine, this enzyme becomes "uncoupled" so that it produces hydrogen peroxide and superoxide, rather than NO.75,138 Importantly, this uncoupling process seems to occur in several common disease states, including hypercholesterolemia,139 hypertension,140 and diabetes, although the mechanisms responsible for this process are poorly understood.

An important source of radicals in the vasculature is the lipoxygenases and in particular 12,15-lipoxygenase. These do not form superoxide, but react directly with unsaturated fatty acids (e.g., linoleic or arachidonic acid) to form a lipid radical (L.), which in turn can react with molecular oxygen to produce alkoxy radicals (LO.) and lipid peroxy radicals (LOO.). These lipid radicals are biologically very active and can stimulate gene expression, consume NO, oxidize NADH, and serve as a source of other radicals.141

Other sources of ROS in vascular cells are xanthine oxidase, cytochrome P450, cyclooxygenase, and mitochondrial electron transport.444 There is now substantial interest in the role of these various sources of ROS and how they contribute to vascular oxidant stress.

In the next several paragraphs, we consider how endothelial dysfunction and vascular smooth muscle abnormalities contribute to several vascular diseases. A recurring theme in these conditions is that ROS play a central role. For example, superoxide rapidly reacts with NO, forming the strong oxidant peroxynitrite. The latter can oxidize lipids, damage lipid membranes, deplete cellular thiols, and alter function of several enzymes.442 This inactivation of NO alters vasomotion and can predispose one to or even cause hypertension.443 A substantial component of VSMC hypertrophy caused by angiotensin II is mediated by hydrogen peroxide.444 ROS also contribute to vascular inflammation by stimulating expression of adhesion molecules in endothelial cells.445 These issues discussed in the context of several vascular diseases.

Atherosclerosis

Atherosclerosis is the prototypical disease characterized by endothelial dysfunction, which may explain many of its cardinal features. Thus, mononuclear and lymphocytic infiltration, hypercontractility, LDL modification, smooth muscle cell growth, and intimal migration are likely related to abnormalities of the endothelium induced by hyperlipidemia, hypertension, smoking, and unknown hereditary factors. The pathogenesis of atherosclerosis viewed as a disease of endothelial dysfunction is depicted in Fig. 6-7. (For a more detailed discussion, see Chap.

Clinically, endothelial dysfunction in atherosclerosis has primarily been defined by impairment of endothelial-dependent relaxation.446 This defect, which likely accounts for the vasospastic tendency of diseased arteries, appears to be attributable to defective generation or delivery of active EDRF/NO.447 Coronary endothelial-dependent vasodilator function is impaired in patients with risk factors such as hypercholesterolemia, prior to angiographically demonstrable coronary disease.448 As previously discussed, increased inactivation of NO by the superoxide anion is likely one cause of this abnormality.447,449 Other causes may include "uncoupling" of the eNOS enzyme, altered calcium signaling of eNOS, and diminished expression of the eNOS enzyme, which clearly occurs late in the atherosclerotic process.450 Of note, LDL and cytokines have been shown to downregulate eNOS by destabilizing the eNOS mRNA. This is prevented by HMG-CoA reductase inhibitors even without lowering of cholesterol. New evidence suggests that this process involves the lipid modification of the small GTPase Rho by the attachment of a geranylgeranyl and lipid moiety, which facilitates its localization to the cell membrane, suggesting a new target for the HMG-CoA reductase inhibitors.454

A second manifestation of a dysfunctional endothelium that is apparent very early after initiation of cholesterol feeding in animals is the recruitment of monocytes and macrophages into the vessel wall.452 This recruitment is likely the result of induction of VCAM-! expression,453 as well as secretion of MCP-!.454 The molecular linkage between hyperlipidemia and MCP-!/adhesion molecule expression is unknown, but may reflect in part the oxidative stress imposed by this change in milieu. Inflammatory cytokines are also important mediators of adhesion molecule expression,455 and their production by the endothelium and inflammatory cells in the vessel wall may also contribute to adhesion molecule expression in both the early and the late stages of the disease.

The intimal proliferation observed in atherosclerotic lesion formation results from migration and hyperplasia of VSMCs456 and accumulation of extracellular matrix.457 Proliferation has been attributed to growth factors such as PDGF, FGF, and IGF-!. Since these growth factors can be produced by the endothelium in vitro, it is very likely that the dysfunctional endothelium in atherosclerosis also produces growth factors while shifting from a growth-inhibitory to a growth-promoting mode. Furthermore, there is evidence that products of oxidative metabolism may also release growth factors and activate matrix metalloproteinases,67 thus contributing to intimal lesion formation on multiple levels.

The recent advances in our understanding of vessel wall biology provide insight into the biological mechanisms responsible for the pathogenesis of atherosclerosis. A unifying concept of the disease has arisen that revolves around endothelial dysfunction mediated by changes in oxidative metabolism. Oxidative stress and oxidatively modified LDL thus assume central roles in atherogenesis Fig. 6-7). As discussed previously, a major source of lipid oxidation is lipoxygenase. Recently, the 12,15-lipoxygenase gene has been deleted in mice. When these animals were crossed with apolipoprotein E-deficient mice (which spontaneously develop atherosclerosis), atherosclerotic lesion development was strikingly reduced.158 These data indicate that 12- and 15-lipoxygenases are almost certainly involved in the atherosclerotic process. The role of oxidized LDL is discussed more completely in Chap. 35, and the relationship of the cell biology of atherosclerosis to coronary ischemic syndrome is discussed in Chap. 41.

Hypertension

Hypertension is characterized by dysfunction of both endothelium and vascular smooth muscle. In chronic hypertension, endothelium-dependent relaxations are impaired in both conduit and resistance arteries.159-162 Relaxations to some platelet factors are also altered, but have been found to be augmented or diminished, depending on the hypertensive model studied.!63 Furthermore, the endothelium-dependent constrictor activity is increased in some models of hypertension.!63 These alterations in endothelial function would tend to increase the tone of hypertensive vessels. The mechanism responsible for this effect is not entirely clear. Data from experimental animals make it seem likely that the alterations in endothelium-dependent responses in hypertension result from a combination of altered endothelial and VSMC function.

Hypertension is also characterized by an increase in vessel wall mass. In the aortas of spontaneously hypertensive and Goldblatt hypertensive rats, this increase can be attributed to an increase in the size of the existing smooth muscle cells.164,165 Hypertrophy is accompanied by an increase in ploidy; that is, an increased DNA content per cell.164,165 In contrast, resistance vessels from these same animals appear to increase their mass by hyperplasia of the smooth muscle cells.166 The stimuli responsible for these changes in the hypertensive vascular wall are unknown. Vascular remodeling appears to have two stages: (1) an initial, reversible intense vasoconstriction mediated by neural or endogenous signals, followed by (2) a remodeling of the vessel wall characterized by increased smooth muscle mass and narrowing of the vessel lumen. There is some evidence that this response is dependent on the presence of the endothelium.127

Vasospasm

When the endothelium becomes dysfunctional as in atherosclerosis, the underlying smooth muscle cells often become hyperreactive to certain vasoconstrictor stimuli, including serotonin and ergonovine.167 Coronary spasm leading to myocardial infarction is one of the most clinically relevant problems arising from this phenomenon. Proposed mechanisms underlying this vasoconstrictor abnormality that can result in total occlusion include supersensitivity of the smooth muscle cells to constrictor stimuli and loss of endothelial-dependent relaxing mechanisms. The increased tendency toward thrombus formation in dysfunctional endothelium, due to a loss of the normal anticoagulant properties, also promotes the release of thrombus-related factors (serotonin, thromboxane A2, ADP, thrombin, and PDGF) in the vicinity of the smooth muscle cells, which can promote vasoconstriction.168

Restenosis

Restenosis is the development of a neointima that occurs following angioplasty, often leading to reocclusion of the initial lesion. The response of the arterial wall to the injury induced by angioplasty (removal of the endothelium and stretching of the vessel wall) involves several distinct events (0-»-B; Fig. 6-7). Removal of the endothelium not only alters the paracrine hormonal environment in which VSMCs exist, but it also exposes a thrombogenic surface to which platelets and other circulating factors can adhere, resulting in the formation of a thrombus. In addition, injury to the underlying smooth muscle may release factors such as FGF, which have mitogenic effects on the remaining smooth muscle cells. Finally, infiltration and subsequent activation of macrophages into the denuded vessel wall bring an additional set of hormonal influences to bear on the vascular smooth muscle. The pathophysiologic consequences of these complex events include migration and proliferation of smooth muscle cells into the intimal area, resulting in the formation of a neointima over a period of weeks to months.

Balloon injury has been extensively studied in several animal models, including pigs, rabbits, rats, and baboons. In the rat carotid artery, the events following injury can be divided into three stages: initial (injury to 48 h), migratory (3 to 7 days), and proliferative (7 days to 3 to 4 weeks). During the initial response to injury, growth-related genes in the smooth muscle cells are induced, including c-fos, PDGF-A, PDGF-ft receptor,!09 and MCP-1.170 It also appears that deep injury to smooth muscle cells results in an outpouring of FGF, a potent smooth muscle mitogen.119 This initial response does not appear to depend on platelet factors, but does appear to be directly related to the removal of the endothelium.106 During the migratory phase, a large increase of thymidine incorporation in the vessel wall occurs, accompanied by further increases in the mRNA encoding IGF-IIZi and the PDGF-i-1 receptor.160 This phase of the response can be modulated by platelet factors and inhibited by the endothelium.106 Finally, the proliferative phase is characterized by marked intimal thickening, with a decreased percentage of thymidine-labeled cells. Some of the increased area is due to deposition of extracellular matrix, and the majority of the proliferative activity occurs at the luminal surface of the vessel. This proliferative phase seems ultimately to be inhibited by regrowth of normal-functioning endothelium.

Thus, during the process of restenosis after angioplasty, both the loss of endothelium and the transformation of smooth muscle cells appear to contribute to neointimal formation. At least two lines of evidence implicate the endothelium as having a crucial role in the response of the vessel wall to injury. First, removal of the endothelium allows initiation of the mitogenic response and, second, regrowth of normal endothelium inhibits further proliferation. Furthermore, gentle denudation with a nylon loop, accompanied by rapid regeneration of endothelium, results in significantly less neointimal proliferation.172 In addition, proliferating smooth muscle cells have characteristics distinct from the differentiated smooth muscle cells in the medial layer. Their cytoskeleton is similar to that found in cultured cells. It seems likely, therefore, that two of the most important causes of restenosis are the loss of endothelium-derived growth-inhibitory factors and the transformation of smooth muscle cells into a phenotype able to respond to platelet- and endothelial-derived factors with proliferation.

ROS are not only thought to be centrally involved in the pathogenesis of atherosclerosis, but very likely are major mediators of the proliferative, hypertrophic, and fibrotic responses that frequently occur in arteries after percutaneous transluminal coronary angioplasty (PTCA) resulting in renarrowing or restenosis of the lumen (see Chap. 45). Migration and growth of VSMCs into the intima contribute significantly to restenosis, and intracellular signaling pathways mediating growth, hypertrophy, and migration are stimulated by ROS.173,174 As discussed previously, both proinflammatory pathways and matrix metalloproteinases, which facilitate vascular remodeling, involve redox-sensitive controlling mechanisms. The apparent broad role for oxidative signaling mechanisms in the vascular wall led to testing of the concept that antioxidants might inhibit restenosis. The production of superoxide is increased in vessels following balloon injury and, in the porcine model of restenosis, vitamins E and C have been shown to reduce neointimal development.175176 Further, several clinical studies have shown that the potent antioxidant probucol reduces late lumen loss after balloon angioplasty.177-179 Larger clinical trials are under way to test the hypothesis that antioxidants are effective in inhibiting the vascular remodeling processes leading to post-PTCA restenosis.

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