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The endothelium: a new target for therapy
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Vascular Medicine
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Vascular Medicine 2000; 5: 49–53
The endothelium: a new target for therapy John P Cooke
Abstract: At one time considered merely a monolayer of cells lining the vascular conduit, the
endothelium has emerged recently as an organ with functions as complex as any in the body.
A highly active regulatory organ, the endothelium senses and assesses the hemodynamic,
humoral, and inflammatory signals to which it is constantly exposed by the blood and responds
by secreting factors that affect vessel tone and structure. These interactions are not merely of
academic interest. It has been increasingly recognized that endothelial dysfunction plays a piv-
otal role in the development and progression of atherosclerosis and coronary artery disease.
Key words: atherosclerosis; l-arginine; nitric oxide; vasodilation
Introduction
The 1980 report by Furchgott and Zawadzki that acetylcho- Maintains vascular smooth muscle toneRegulates angiogenesis, cell proliferation line brings about vascular relaxation only when the endo- Mediates inflammatory and immune responses thelium is intact was a seminal finding in contributing to our understanding of cardiovascular homeostasis.1 Specifi- cally, it was discovered that the ability of acetylcholine to relax isolated rabbit aorta and other vessels depends on the Regulates platelet adhesion and aggregationRegulates lipid oxidation integrity of the endothelial cells in the preparations. Indeed,once these cells were removed, as occurs in endothelialinjury, acetylcholine paradoxically induced arteries tocontract.1 leukocytes) (Table 2).3,4 Normally the endothelium func- Experiments that built on this work and continue through tions as an inhibitor, placing constraints on smooth muscle the present have confirmed the importance of the endo- contraction, platelet aggregation, vascular smooth muscle thelium as a mediator of vascular tone – vasodilation and growth, thrombosis, and monocyte adhesion.5 vasocontraction. A large body of research has demonstrated The equation is therefore generally balanced on the side that this organ responds to hemodynamic influences as well of promoting vasodilation and inhibiting cellular prolifer- as a host of neurohumoral and inflammatory factors to per- ation. But given changes in environment, such as that induced by hypercholesterolemia or hypertension, the bal-ance can shift to permit vasoconstriction, thrombosis, and Functions of the normal endothelium
A partial list of endothelium-derived products.
The endothelium is the largest organ in the body, equivalent in size to approximately six tennis courts. It exerts controlover an array of synthetic mechanisms, all of which serve Vasodilator; inhibits VSM growth; anti-platelet; to maintain vascular tone and blood fluidity and provide homeostasis in the event of intimal injury. Thus, the endo- Vasodilator; inhibits VSM growth; anti-platelet; thelium has a prominent role in angiogenesis, lipoprotein metabolism, capillary transport, vasomotion, vascular struc- ture, and in the general mediation of interactions between circulating blood and the vessel wall (Table 1).3 Vasoconstrictor; activates platelet aggregation In presiding over this range of vascular functions and responding to a local environment, the endothelium pro- duces a formidable array of agents that influence vascular tone and structure, as well as the interaction of the vessel wall with circulating blood elements (platelets and Division of Cardiovascular Medicine, Stanford University School of Medi- NO, nitric oxide; VSM, vascular smooth muscle; PGI , prostacyclin; EDHF, endothelium-derived hyperpolarizingfactor; AM, adrenomedullin; CNP, natriuretic peptide; TxA , Address for correspondence: John P Cooke, Division of Cardiovascular thromboxane A ; ET, endothelin; AII, angiotensin II; PAI-1, Medicine, Stanford University School of Medicine, 300 Pasteur Drive, plasminogen activator inhibitor; vWF, von Willebrand factor; initiation of the cell cycle. Alteration of endothelial func- Hemodynamics and vascular remodeling
tion is now recognized to play an important role in thepathogenesis of vascular disease.3,5 Its strategic position between the circulating blood and vas- Maintaining vascular tone is a crucial endothelial func- cular smooth muscle makes the endothelium a likely target tion, accomplished through synthesis and release of sub- organ for mechanical stress and vascular injury. But the site stances known as endothelium-derived relaxing (EDRFs) also confers the capacity to sense changes in hemodynamic and contracting factors (EDCFs). Vascular tone depends on forces – flow (shear stress) and pressure (strain) – and maintaining a balance between these substances. The most accordingly adjust vascular smooth muscle tone. The endo- potent of the vasoregulators had been known as EDRF and thelium serves as a mechanosensor of flow rate and press- is now identified as nitric oxide (NO).
ure, mediating the opposing effects of these hemodynamic Other vasodilators released by the endothelium allow it forces on vascular tone. This unique function of the endo- to act via several molecular and physiologic avenues; for thelium fine tunes vascular tone to varying hemodynamic example, prostacyclin, endothelium-derived hyperpolariz- ing factor, adrenomodulin, and natriuretic peptide. On the An increase in blood flow or its pulsatility stimulates other side of the equation, the endothelium generates the release of prostacyclin (PGI2) and NO in a functioning EDCFs, among them endothelin, thromboxane A2, and endothelium, causing vasodilation. Indeed, mechanical shear stress resulting from increased blood flow is a potentstimulus for the release of NO,13 and areas of blood vesselsexposed to high laminar flow produce more nitric oxide; Nitric oxide: an endogenous vasodilator
intriguingly, these areas are often free of atheroscleroticplaque.
The vasodilatory substance discovered by Furchgott and Disturbances in flow-mediated vasodilation have patho- Zawadzki and subsequently designated EDRF was ident- physiologic and clinical consequences. In patients with cor- ified as nitric oxide or a NO-containing donor in 1987.6,7 onary artery disease (CAD) and impairment of endothelial Endogenous NO is synthesized from the metabolism of l- vasodilator function, increases in blood flow through the arginine, an essential amino acid, to l-citrulline by the diseased coronary artery cause a paradoxical vasoconstric- tion, which can contribute to myocardial ischemia during Endothelium-derived NO is the most potent endogenous vasodilator in the body. The endothelium synthesizes andreleases NO in response to a variety of stimuli – chemical,humoral, and physical: platelet products, thrombin, hor- Endothelial dysfunction and disease
mones, neurotransmitters, local autacoids, changes in oxy- gen tension, and increases in flow. NO directly causes theunderlying smooth muscle to relax. Endothelial release of Given the number and range of processes in which the NO counters the vasoconstrictive effects of norepinephrine, endothelium participates, endothelial dysfunction can be serotonin, vasopressin, angiotensin II, and endothelin.3,4 expected to have major pathophysiologic implications. Evi- These vasoconstrictors act directly on the vascular smooth dence suggests that disruptions in normal endothelial func- muscle, causing it to contract, but they also stimulate recep- tion play a part in a number of diseases; for example, hyper- tors on the endothelium, which counteracts the vasoconstr- tension, diabetes, hypercholesterolemia, and coronary Nitric oxide is also antithrombotic, through its ability to If normal endothelial function depends on constant fine inhibit the adhesion and aggregation of platelets. This it tuning and adjustment of opposing forces and effects, dys- achieves together with prostacyclin, the two interacting function might best be defined as an imbalance – between synergistically through different mechanisms to inhibit plat- relaxing and contracting factors, between anti- and proco- elet aggregation.9,10 They also inhibit leukocyte–vessel wall agulant mediators, or between growth-inhibiting and interactions, preventing the adherence of leukocytes and growth-promoting factors. Synthesis or release of protec- thereby contributing to the anti-inflammatory activities of tive factors can be impaired; synthesis or release of con- tracting, procoagulant, and growth-promoting substances Studies that examine in vitro effects of NO have demon- strated its capacity to suppress several of the key processes The endothelial dysfunction that occurs in atherosclerosis in atherogenesis – cell proliferation and adhesion, platelet and hypercholesterolemia has received the most attention.
adhesion and aggregation, monocyte adhesion and chemo- Impaired endothelium-dependent relaxation, as assessed by taxis, and inhibition of superoxide anion generation. It fol- vasoconstrictive response to acetylcholine, has been lows that reducing the activity of vascular NO would pro- observed in humans with coronary atherosclerosis or hyper- mote atherogenesis. Indeed, a reduction in the activity of cholesterolemia.14,15 Intracoronary acetylcholine causes a vascular NO is one of the earliest abnormalities to occur vasoconstriction of angiographically normal left anterior in hypercholesterolemic animals and humans; the evidence descending arteries in patients with hypercholesterolemia.14 for reduction is impaired endothelium-dependent vaso- Indeed, total occlusion of the distal left anterior descending dilation, which occurs well before any structural changes artery may occur in response to acetylcholine in hypercho- can be observed in the vessel wall. Considering, then, the lesterolemic patients with no angiographic evidence of actions of NO in the aggregate, it seems reasonable to pos- atherosclerosis. By contrast, in normal individuals, the tulate that endothelium-derived NO is an endogenous anti- diameter of the epicardial coronary arteries increases in Vascular Medicine 2000; 5: 49–53
The endothelium: a new target for therapy Thus, hypercholesterolemia causes significant endo- reduce the release of endothelium-derived NO. Endothelial thelial vasodilator dysfunction in coronary arteries without function is impaired in experimental models of diabetes angiographic evidence of atherosclerosis – and in the mellitus, and endothelium-dependent and -independent absence of other risk factors for coronary artery disease.
vasodilation are compromised in patients with non-insulin- That the abnormal endothelial response apparently precedes dependent diabetes mellitus. In both cases, the cause the development of atherosclerosis suggests that it may play appears to be an abnormality in the NO pathway.
a role in the initiation and progression of atheroscler-osis.12,16 In addition to impaired vasodilation, it is apparent that Risk factors for endothelial dysfunction
the primary pathogenic processes observed in atherogen-esis – smooth muscle proliferation, platelet and leukocyte Coronary artery disease and endothelial dysfunction share adhesion and aggregation, inflammation – are precisely risk factors, notably hypercholesterolemia and cigarette smoking. Hypercholesterolemia is a well-established risk The relationship between abnormal endothelial function factor for the development of CAD in humans; it also atten- and abnormal plasma lipids remains ill-defined, but it is uates endothelium-dependent vasorelaxation and augments likely that low-density lipoprotein (LDL) is involved. Sev- response to vasoconstrictor agents in animal models.2 In eral studies have shown that endothelium-dependent relax- ation is impaired if the blood vessel wall is exposed to impaired, and the availability of NO and resulting effects oxidized LDL; it now appears that oxidized LDL or other oxygen-derived free radicals (e.g. superoxide anion) may Likewise, cigarette smoking is a risk factor for athero- inactivate NO.3–5,16 Exposure of the endothelium to elev- sclerosis, CAD, and endothelial dysfunction. Several ated levels of LDL cholesterol causes an alteration in endo- effects of smoking have been proposed as the causative thelial function characterized by increased generation of mechanism: according to one theory, toxic components of superoxide anion, more rapid degradation of NO, and, later, cigarette smoke may induce oxidative stress and thereby reduced synthesis of NO. The imbalance between superox- cause endothelial damage, perhaps helping to initiate the ide anion and nitric oxide causes a change in the oxidative development of an atherosclerotic plaque. In addition, a state of the endothelial cell that triggers the expression of study of 200 cigarette smokers aged between 15 and 57 redox-sensitive genes that encode adhesion molecules and years suggests that endothelial dysfunction may occur even chemokines.16 The endothelium begins to express these in light smokers as early as adolescence, although the likeli- adhesion molecules and chemokines, which attract circulat- hood of endothelial dysfunction increases with increasing ing monocytes. The monocytes begin to adhere and pen- etrate into the subendothelial space. Once there, the mono- A number of metabolic alterations in animal models that cytes become tissue macrophages, and scavenge oxidized are associated with endothelial elaboration of superoxide LDL cholesterol. The tissue macrophages evolve into lipid- anion predispose to atherogenesis, including hypertension, laden foam cells; concentrations of foam cells form the first which is an independent risk factor for coronary events.
visible lesions of atherosclerosis – the fatty streak.
Reduced EDRF (NO) can be shown in patients with hyper- Abnormal cellular proliferation contributes to the pro- tension and left ventricular hypertrophy, contributing to cess: growth factors released by endothelial cells, platelets, large and small vessel vasoconstriction and myocardial and macrophages promote smooth muscle proliferation.
The proliferating smooth muscle cells synthesize extra- relaxation has been shown in the peripheral vasculature in cellular matrix proteins, and, over time, an atherosclerotic hypertensive patients, future studies must decide which is plaque develops. Angioplasty may simulate the process in a considerably shorter time. Balloon injury to the endo-thelium and vascular smooth muscle cells accelerates cellu-lar proliferation, and restenosis is the result.3,4 Diagnosis
Disturbances in NO activity can be expected to play a critical role in a number of disease states. For example,systemic vasoconstriction is a hallmark of advanced chronic In light of the critical importance of the endothelium, congestive heart failure, the end stage of the CAD con- assessment of endothelial function is one of the tasks facing tinuum. In clinical studies of heart failure, stimulated clinicians. Routine clinical evaluation of endothelial func- release of EDRF (NO) appears to be reduced. Long-term tion is not yet available, but assessment of impaired endo- reduced blood flow, exacerbated by limited physical thelium-dependent vasodilation in large arteries has been activity, may contribute to endothelial dysfunction in achieved using arteriography, ultrasound, plethysmography, and measurements of urinary nitrogen oxides and cyclic Data for hypertension are more difficult to interpret.
GMP. Under development are intravascular probes which Although it has been shown that endothelium-dependent contain porphyrin-based electrodes that can directly meas- vasodilation is abnormal in hypertension, it has yet to be determined whether endothelial dysfunction in humans pre-cipitates the development of elevated blood pressure or issecondary to hypertension.
Future therapeutic strategies
Insulin has been shown to produce endothelium-depen- dent relaxation of isolated arteries in humans, whereas Growing knowledge of the multiple functions of the endo- increasing concentrations of glucose have been observed to thelium has also focused attention on strategies that may Vascular Medicine 2000; 5: 49–53
improve endothelial function.20 Both non-pharmacologic seems to be enhanced with consistent exercise, and endur- and pharmacologic interventions have been proposed capacity for coronary vasodilation than their sedentary age-matched counterparts.25 Non-pharmacologic strategies
Non-pharmacologic approaches to improving endothelial
Pharmacologic strategies
function are based on findings in animal models, epidemiol- Pharmacologic measures may be called upon when lifestyle ogic data, and some limited studies in humans. Perhaps changes, dietary supplements, or other non-pharmacologic foremost among these approaches is smoking cessation.
measures fall short of the desired goal. Whereas no endo- Former smokers have shown evidence of better endo- thelium-targeted medications have yet been developed, thelium-dependent function, i.e. flow-mediated dilation, existing drugs developed for other purposes have been than have current smokers,18 suggesting that the effects of shown to improve endothelial function. For example, lipid- cigarette smoking on vascular pathology may be reversible.
lowering agents like HMG-CoA reductase inhibitors Dietary measures to reduce serum cholesterol may improve endothelium-dependent coronary vasomotion (see improve endothelial function. In hypercholesterolemic monkeys, a low-cholesterol diet reduces LDL levels, nor- In addition to their antihypertensive effects, angiotensin- malizes endothelial vasodilator function, and causes converting enzyme (ACE) inhibitors appear to improve regression of atherosclerotic lesions.21 In humans, transient endothelial dysfunction. ACE, which figures prominently impairment of endothelial function in normolipidemic sub- in the renin–angiotensin system, promotes vasoconstriction jects has been demonstrated following a 900-calorie high- by converting angiotensin I to angiotensin II – a powerful fat meal, adding to the evidence building against dietary vasoconstrictor – and by inactivating bradykinin, thereby fat.23 Flow-mediated brachial artery vasoactivity took about nullifying its vasodilatory effect and preventing its acti- 6 hours to return to preprandial levels.
vation of l-arginine to the NO pathway. Drugs that inhibit ACE prevent the degradation of bradykinin and the forma- precursor) may also be useful.20,22 In hypercholesterolemic tion of angiotensin II. The recent TREND (Trial on Revers- animals and humans, oral l-arginine supplementation ing Endothelial Dysfunction) study demonstrated that treat- restores endothelial vasodilator function. In hypercholester- olemic animal models, chronic administration of l-arginine endothelial function in normotensive patients with estab- slows progression, and can induce regression of vascular lished coronary atherosclerosis and CAD.27 Calcium channel blockers constitute another drug cate- Antioxidant therapy is another avenue that merits atten- gory that exerts an antiatherogenic effect apart from its anti- tion, considering that oxidation of LDL plays an important hypertensive action. Studies with cholesterol-fed, hypercho- part in endothelial disruption. Epidemiologic studies, more- lesterolemic rabbits suggest that treatment with calcium over, have suggested that dietary antioxidants – vitamin antagonists may slow the development of atherosclerosis supplements or foods high in vitamin A, E, C, and others – and partially preserve endothelium-dependent relaxation. In have a negative correlation with CAD.
humans, calcium channel blockers have been shown to Fish consumption and the incidence of CAD are retard the development of new atherosclerotic lesions.
inversely related. Studies of the coronary circulation in pigs However, calcium channel blockers have not been shown have shown that a diet rich in fish oil augments release of to increase longevity in these patients (although diltiazem endothelial-dependent NO and lessens platelet responsive- Increased physical activity may improve endothelial Estrogen has long been thought to confer a cardioprotec- function. In athletes, endothelium-dependent relaxation tive effect, borne out by the lower frequency of coronaryatherosclerosis in premenopausal women. Studies in female monkeys and other animals indicate that estrogens exert a beneficial effect on coronary vasomotion.29 The beneficialeffects of estrogen may be due in part to its effect on the lipid profile, but it also enhances the expression of NO syn- thase, and by virtue of its antioxidant properties, may pro- Modify diet: reduce fat intake and add fish/fish oil to diet l-arginine supplements; antioxidant supplementsPhytochemicals/phytoestrogens with antioxidant Physicians will become increasingly aware of the role of the endothelium as a mediator of critical functions in health and as a source of far-reaching pathogenic effects in dis- ease. An organ with numerous regulatory functions, the Lipid-lowering agents: e.g. HMG-CoA reductase endothelium controls vascular tone, cell growth, and throm- botic and inflammatory mechanisms. Impairment of theendothelium contributes to the development and pro- ACE, angiotensin-converting enzyme; HMG-CoA, 3-hydroxy-3- Assessment and management of endothelial dysfunction Vascular Medicine 2000; 5: 49–53
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Vascular Medicine 2000; 5: 49–53

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