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• W2137788779 abstract "The endothelium is a crucial vascular structure not only because it serves as a barrier between flowing blood and vascular wall but also because it produces mediators regulating vascular growth, platelet function, and coagulation. In addition, it alters vasomotor tone by synthesising and metabolising vasoactive substances including an endothelium-derived hyperpolarising factor, prostacyclin, and, most notably, endothelium-derived relaxing factor (EDRF), which has been identified as nitric oxide or a related compound.1Bassenge E Busse R Endothelial modulation of coronary tone.Prog Cardiovasc Dis. 1988; 5: 349-380Summary Full Text PDF Scopus (169) Google Scholar NO, which is formed from L-arginine by the action of a constitutive form of the enzyme nitric oxide synthase,2Palmer RMJ Ashton DS Moncada S Vascular endothelial cells synthesize nitric oxide from L-arginine.Nature. 1988; 333: 664-666Crossref PubMed Scopus (4086) Google Scholar inhibits platelet aggregation and adhesion, modulates smooth muscle cell proliferation, attenuates the generation of endothelin, and modulates leucocyte and monocyte adhesion to the endothelium—all of which are cardinal features in the pathogenesis of atherosclerosis. Thus, in addition to its vasorelaxing effects (via stimulation of guanylate cyclase to increase cyclic GMP in the vascular smooth muscle), NO seems to exert potent antiatherosclerotic functions. There is nothing new in the notion that endothelium is central to the pathogenesis of atherosclerosis; however, the old assumption that endothelial desquamation precedes lesion development has given way to the concept of dysfunction of the endothelium, since even advanced lesions may be covered by an intact, albeit morphologically altered, endothelial cell layer. As discussed by Peter Libby (p s4), atherosclerosis is increasingly being viewed as an inflammatory disease. The metabolic stress imposed on the endothelium by various risk factors and the concomitant excessive production of reactive oxygen species by the endothelium itself seem to recruit inflammatory cells into the atherosclerotic vascular wall via stimulation of redox-sensitive genes.3Berliner JA Navab M Fogelman AM et al.Atherosclerosis: basic mechanisms.in: Oxidation, inflammation, and genetics. Circulation. 91. 1995: 2488-2496Google Scholar Thus, the endothelium is not only a target but also a mediator of atherosclerosis. Importantly, NO, being a radical itself, avidly reacts with oxygen free radicals and thereby interferes with redox-sensitive mechanisms. Indeed, our group has shown that NO inhibits the activation of NF-κB-like transcriptional regulatory proteins, which are activated by reactive oxygen species and mediate transcription of numerous genes implicated in the pathogenesis of atherosclerosis.4Zeiher AM Fisslthaler B Schray-Utz B Busse R Nitric oxide modulates the expression of monocyte chemoattractant protein 1 in cultured human endothelial cells.Circ Res. 1995; 76: 980-986Crossref PubMed Scopus (382) Google Scholar These findings pointed towards a molecular link between endothelial NO synthesis and oxidant-sensitive transcriptional regulatory mechanisms involved in the protective effects of intact endothelial function. Excessive production of endothelial reactive oxygen species probably accounts also for the impaired endothelial vasodilator function characteristic of atherosclerotic or even risk-factor-exposed vessels, since scavenging of oxygen radicals by NO will reduce the bioavailability of NO to mediate vascular relaxation. In the aggregate, these data led to the hypothesis that the abnormal redox state in the vascular endothelium, as the fundamental metabolic feature of atherosclerosis, not only contributes to the pathogenesis of atherosclerotic lesions but also mediates the impaired control of vasomotor tone in coronary artery disease, establishing a mechanistically unifying relation between atherosclerosis and endothelial vasodilator dysfunction. In this article I relate new concepts of endothelial vasodilator dysfunction to the ischaemic manifestations of coronary artery disease. Early in the 1980s it became apparent that myocardial ischaemia is not necessarily the consequence of a failure of coronary blood flow to increase in response to an augmented demand. Instead it quite commonly results from a transient impairment of coronary blood supply, possibly due to inappropriate vasoconstriction.5Epstein SE Talbot TL Dynamic coronary tone in precipitation, exacerbation and relief of angina pectoris.Am J Cardiol. 1981; 48: 797-803Summary Full Text PDF PubMed Scopus (140) Google Scholar Furchgott and Zawadzki's observation6Furchgott RF Zawadzki JV The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.Nature. 1980; 288: 373-376Crossref PubMed Scopus (9872) Google Scholar that vascular tone can be modulated by a factor released from the endothelium—now identified as NO or a related compound—opened new avenues for investigating the regulation of coronary blood flow. NO proved to mediate the vasodilation produced by various neurohumoral substances, platelet-derived products, and coagulation factors, while attenuating vasoconstriction caused by other mediators; and these findings suggested that endothelial vasodilator function represents a negative feedback mechanism to prevent vasoconstriction and thrombus formation at sites of normal endothelium. Indeed, experimental removal of the endothelium, or injury to it, converted vasodilator effects into vasoconstrictor effects. In patients with early coronary atherosclerosis, progressive impairment in endothelial dilator functions is observed.7Zeiher AM Drexler H Wollschläger H Just H Modulation of coronary vasomotor tone in humans: progressive endothelial dysfunction with different early stages of coronary atherosclerosis.Circulation. 1993; 83: 391-401Crossref Scopus (924) Google Scholar In addition, there are numerous reports of local endothelial vasodilator dysfunction in atherosclerotic or even risk-factor-exposed coronary arteries, with inappropriate vasoconstriction in response to stimuli such as exercise, pacing, cold pressor testing, mental stress, and intracoronary thrombus formation8Meredith IT Yeung AC Weidinger FF et al.Role of impaired endothelium-dependent vasodilation in ischemic manifestations of coronary artery disease.Circulation. 1993; 87: V, 56.V.66Google Scholar—all of which can precipitate angina and myocardial ischaemia in coronary artery disease. Thus, the hypothesis was quickly put forward that endothelial vasodilator dysfunction of atherosclerotic epicardial arteries—unbalancing vascular tone towards vasoconstriction—is responsible for transient impairment of coronary blood supply. The impairment of endothelial vasodilator function in atherosclerosis seems to be related to decreased bioactivity rather than to reduced production of NO or alterations of NO-synthase. Enhanced destruction of NO is associated with increased endothelial synthesis of free radicals, especially superoxide anions.9Ohara Y Peterson TE Harrison DG Hypercholesterolemia increases endothelial superoxide anion production.J Clin Invest. 1993; 91: 2546-2551Crossref PubMed Scopus (1634) Google Scholar Importantly, both experimental and preliminary clinical data indicate that scavenging of superoxide anions ameloriates the endothelial vasodilator dysfunction of atherosclerotic epicardial vessels. Thus, the extent of endothelial vasodilator dysfunction might reflect the oxidative stress imposed on the endothelium by risk factors and by the atherosclerotic process itself, again pointing to a molecular link between vasomotor dysfunction and the pathogenesis of atherosclerosis. Although epicardial conductance vessels, where atherosclerotic lesions develop and inappropriate vasoconstriction is observed, contribute only 10–15% of total coronary vascular resistance, impaired endothelial vasodilator function superimposed on even a moderate stenosis might be an important mechanism of myocardial ischaemia. Luminal diameter reductions produced by clinically relevant stimuli are usually less than 20%, but such an increase in arterial tone might be enough to convert a haemodynamically insignificant lesion into a flow-limiting stenosis—since, for 'example, the resistance to flow offered by a stenosis is expected to quadruple as the degree of diameter narrowing increases from 70 to 90%, with ensuing reductions in resting blood flow. All these observations point to a pathogenetic link between endothelial vasodilator dysfunction and the variation in ischaemic threshold in patients with moderate coronary stenoses. However, in the absence of moderate-to-severe stenoses, such inappropriate vasoconstriction of epicardial arteries is insufficient to explain transient impairment of coronary blood flow. Moreover, the atherosclerotic process itself is associated with both structural and functional alterations of the vascular wall, which will counteract vasoconstriction in the presence of endothelial vasodilator dysfunction. Atherosclerosis leads to atrophy of the medial smooth muscle layer and to increased stiffness of the vascular wall, both of which would lessen the response to vasoconstrictor stimuli. Atherosclerotic coronary arteries undergo a structural remodelling process characterised by compensatory enlargement of segments to preserve the luminal diameter despite an increase in the size of the plaque.10Gibbons GH Dzau VJ The emerging concept of vascular remodeling.N Engl J Med. 1994; 330: 1431-1438Crossref PubMed Scopus (1328) Google Scholar In addition, there is a functional remodelling process characterised by a decrease in coronary vasomotor tone as atherosclerotic plaque load increases.11Schächinger V Zeiher AM Quantitative assessment of coronary vasoreactivity in humans in vivo: importance of baseline vasomotor tone in atherosclerosis.Circulation. 1995; 92: 2087-2094Crossref PubMed Scopus (90) Google Scholar In the aggregate, the effects of atherosclerosis in vivo are clearly different from those of simple removal of the endothelium. Thus paradoxical vasoconstriction of epicardial conductance vessels, due to endothelial vasodilator dysfunction, is unlikely to contribute greatly to the ischaemic manifestations of coronary artery disease. What, then, is the culprit lesion? There is now evidence that localised chronic inflammatory processes within the atherosclerotic plaque, rather than the endothelium, are responsible not only for plaque rupture itself but also for the hyperreactivity of these vessels to vasoconstrictor stimuli.12Zeiher AM Geobel H Schächinger V Ihling C Tissue endothelin-1 immunoreactivity in the active coronary atherosclerotic plaque: a clue to the mechanism of increased vasoreactivity of the culprit lesion in unstable angina.Circulation. 1995; 91: 941-947Crossref PubMed Scopus (278) Google Scholar Finally, the syndrome of variant angina, which is characterised by frank coronary spasm and might be viewed as the extreme end of the spectrum of inappropriate epicardial artery constriction, appears to be due to hyperreactivity of the smooth muscle cells and not to endothelial vasodilator dysfunction. Although endothelial vasodilator dysfunction of epicardial arteries does not seem responsible for acute ischaemic syndromes, such dysfunction is not confined to these conductance vessels prone to atherosclerosis; it may extend into the coronary microcirculation, where no overt atheroma develops but where coronary blood flow, and hence myocardial perfusion, is determined. Endothelial vasodilator dysfunction of coronary resistance vessels seems to be a major determinant of myocardial ischaemia during increased metabolic demand. Inhibition of NO synthesis increases coronary vascular resistance by more than 20%, so basal production of NO clearly contributes to the regulation of myocardial perfusion. However, resistance-vessel tone is probably affected by other endothelial mediators too. Impaired endothelial vasodilation of the coronary microcirculation has been demonstrated in some patients with normal coronary arteries but with evidence of myocardial ischaemia as detected by myocardial lactate production.13Egashira K Inou T Hirooka Y Yamada A Urabe Y Takeshita A Evidence of impaired endothelium-dependent coronary vasodilation in patients with angina pectoris and normal coronary angiograms.N Engl J Med. 1993; 328: 1659-1664Crossref PubMed Scopus (506) Google Scholar More importantly, the coronary microcirculation of some patients with atherosclerosis has shown impairment of endothelial vasodilator capacity—evidence that the functional consequences of atherosclerosis extend into the coronary microcirculation. It is exactly those patients who show a paradoxical decrease in coronary blood flow during increased metabolic demand, as well as exercise-induced thallium-perfusion defects indicative of myocardial ischaemia.14Zeiher AM Krause T Schächinger V Minners J Moser E Impaired endothelium-dependent vasodilation of coronary resistance vessels is associated with exercise-induced myocardial ischemia.Circulation. 1995; 91: 2345-2352Crossref PubMed Scopus (318) Google Scholar These findings suggest a crucial role for endothelium-dependent vasodilation of coronary resistance vessels in coupling metabolic demand and coronary blood flow. Indeed, Quyyumi et al15Quyyumi AA Dakak N Andrews NP Gilligan DM Panza JA Cannon III, RO Contribution of nitric oxide to metabolic coronary vasodilation in the human heart.Circulation. 1995; 92: 320-326Crossref PubMed Scopus (271) Google Scholar lately established that coronary blood flow regulation during increased myocardial demand is largely mediated by NO. However, neither the mechanism nor the precise site or vessel size of the resistance vasculature affected has yet been elucidated; moreover, we do not know whether the impaired dilator response originates from functional alterations of the microvascular endothelium itself or is mediated by factors released upstream in the atherosclerotic conductance vessels and acting downstream in the resistance vasculature. Interestingly, hypercholesterolaemia, advanced age, and diabetes selectively impair endothelial dilator functions not only of coronary but also of forearm resistance vessels, so the functional impairment seems to be general.16Zeiher AM Drexler H Saurbier B Just H Endothelium-mediated coronary blood flow modulation in humans.in: Effects of age, atherosclerosis, hypercholesterolemia, and hypertension. J Clin Invest. 92. 1993: 652-662Google Scholar Whatever the mechanisms, endothelial vasodilator function of coronary resistance vessels will not only contribute to ischaemic manifestations of coronary artery disease in the absence of haemodynamically significant stenoses but may also aggravate ischaemic episodes in patients with advanced coronary artery disease—eg, during plaque-rupture-mediated epicardial artery thrombus formation with subsequent release of platelet-derived vasoconstrictors acting downstream on the vascular wall of resistance vessels. Further insights can be derived from therapeutic interventions to improve endothelial vasodilator function. Effective lipid lowering normalises endothelial vasodilator function in the coronary microcirculation and ameliorates the vasoconstrictor responses of epicardial conductance vessels.17Levine GN Keaney Jr, JF Vita JA Cholesterol reduction in cardiovascular disease.in: Clinical benefits and possible mechanisms. N Engl J Med. 332. 1995: 512-521Google Scholar This functional improvement in the regulation of coronary vasomotor tone is accompanied by improved myocardial perfusion during increased myocardial demand and is associated with a reduction in transient myocardial ischaemia during daily life (as assessed by ST analysis of Holter recordings). The added beneficial effect of antioxidant treatment18Anderson TJ Meredith IT Yeung AC Frei B Selwym AP Ganz P The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion.N Engl J Med. 1995; 332: 488-493Crossref PubMed Scopus (1097) Google Scholar offers support for the pivotal role of an abnormal redox state in the vascular endothelium, mediating impaired control of vasomotor tone in atherosclerotic coronary arteries. However, further studies will be necessary to determine whether improvement of redox equilibrium by risk factor modification will translate into plaque stabilisation and a reduction of ischaemic events.19Benzuly KH Padgett RC Kaul S Piegors DJ Armstrong ML Heistad DD Functional improvement precedes structural regression of atherosclerosis.Circulation. 1994; 89: 1810-1818Crossref PubMed Scopus (106) Google Scholar If such proof were forthcoming, the assessment of endothelial vasodilator function would emerge as an indispensable diagnostic and prognostic tool in coronary artery disease." @default.
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• W2137788779 title "Endothelial vasodilator dysfunction: Pathogenetic link to myocardial ischaemia or epiphenomenon?" @default.
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