Endothelial Dysfunction in Arterial Hypertension

Home , Endothelial dysfunction, Endothelium

F Contreras, M Rivera, J Va´squez, MA De la Parte and M Velasco School of Medicine, Universidad Central de Venezuela, Venezuela

Systemic arterial pressure is a dynamic and reactive and mortality of cardiovascular origin. These three physiological parameter depending on a great many fac- elements are closely related and frequently act simul- tors. The endothelial cells of the vascular system are taneously damaging different organs. In this paper we responsible for many biochemical reactions maintaining review the physiology of the endothelium and the prob- vascular homeostasis and therefore arterial pressure. able consequences of endothelial dysfunction on the Arterial hypertension, atherosclerosis and endothelial pathophysiology of arterial pressure. Journal of Human dysfunction constitute risk factors increasing morbidity Hypertension (2000) 14, Suppl 1, S20–S25.

Keywords: endothelium: endothelial dysfunction; arterial hypertension; atherosclerosis; nitric oxide

Introduction the vessel. In small vessels these cells possess a definite basal membrane underneath which fine The discovery of the endothelium as the main regu- elastic fibrils extend (subendothelium) establishing lator of vascular tone has produced an enormous contact with the smooth muscle cells of the media. amount of clinical research trying to explain the Such fibrils normally look like a continuous, retrac- physiology of this organ and its pathophysiology tile stripe, the inner elastic membrane. It is parti- related to arterial hypertension. cularly conspicuous in the muscle arteries of The endothelial cells of the vascular system are medium thickness disappearing into the capillaries. responsible for many biological activities that hold Collagen and elastin fibrils derive from mesenchy- vascular homeostasis. However, its dysfunction, mal cells of fibrocytic or smooth muscle type within which causes changes of modulation of the contrac- an amorphous, basal substance, rich in acid muco- tile state of a vessels smooth muscle, is according to polysacharides. The amount of collagen and basal experimental evidence closely associated with the 1,2 substance increases with age. appearance of premature arteriosclerosis and, in The media consists of smooth muscle cells and time, of arterial hypertension. The occurrence of elastic fibrils and the adventitia, the external coat of hypertension and atherosclerosis increases with 3 the arteries, is made of collagen fibrils, fibroblasts, age and in most cases arterial hypertension aggra- nervous fibrils and small blood vessels.4 The endo- vates atherosclerotic injuries present in blood ves- thelium is arranged in such a way that it forms a sels as well as accelerating pathological changes of monolayer covering the internal surface of arteries, structure and function in ‘target’ organs. Much evi- veins, lymphatic vessels, cavities and cardiac valves dence also demonstrate clearly that endothelial dys- as well as the cavernous body (corpus cavernosum) function brings about a thickening of the subendo- of the penis and clitoris, anterior eye chamber, ple- thelial sheet, increased amounts of proteins, lipids ura, lungs, and pericardial cavity, etc. Embryologi- and proinflammatory cells together with changes of cally the endothelium stems from mesoderm and viscoelastic properties of the arterial wall inducing weighs about 2 kg. The functional unit of the endo- alterations of the reactions to vasoactive stimuli. In thelium, the endothelial cell, is polyhedral in shape this review we analyse the underlying pathophysiol- showing a central thickness around 3 to 4 ␮m and ogical mechanisms that relate endothelial dysfunc- 0.1 ␮m at the edges. Usually the endothelium is tion with arterial hypertension. accompanied by a satellite cell, the periocyte, a cell present in blood and lymphatic vessels supporting What is the endothelium? and retaining the vascular tone. Usually three sheets are distinguished on the wall of any blood vessel: intima, media and adventitia. Functions of the vascular endothelium Blood vessels, except sinusoids, are covered with a The endothelium is the basic structure of the intima unique, continuous sheet of very specialized, meta- pursuing a control function on circulation through bolically active, polyhedral cells, the endothelial the production of various vasoactive substances. In cells, positioned parallel to the longitudinal axis of addition, it manufactures substances with enzymatic and immunological activity. Likewise the Correspondence: Professor M Velasco, Torre Domus, Avenida endothelium is visualized as a highly selective per- Abraham, Lincoln c/Olimpo, Piso 6 Ofic 6A, Sabana Grande, meable barrier exerting a fundamental role upon the Caracas, Venezuela control of biochemical processes in blood, helping Endothelial dysfunction in arterial hypertension F Contreras et al S21 by this means to maintain vascular homeostasis Table 2 From endothelium released substances (Table 1). The endothelium possesses very specific charac- Vasodilators Vasoconstrictors teristics like the production of autacoids with antag- ¼ onistic effects involved in tone control and vascular Nitric oxide Angiotensin I and II ¼ Bradykinin Endothelin homeostasis. It also has regulatory influences on ¼ Prostacyclin Thromboxane A2 vascular rearrangement, fibrinolysis, adhesion of ¼ Hyperpolarizing factor Arachidonic Acid leucocytes and activated platelets to the endo- derived from endothelium Prostaglandin H2 5 ¼ Serotonin Thrombin thelium and on inflammatory processes. In ¼ response to a variety of chemical and physical stim- Histamine, Substance P Nicotine uli the endothelium produces a great deal of vasoac- Inhibitors of smooth muscle Promotors of smooth muscle tive and growth modulating substances as well as growth growth ¼ Nitric oxide Platelet-derived growth factor other factors mediating such functions as nitric ¼ Prostacyclin Basic fibroblast growth factor oxide (NO), a known vasodilator6 (Table 2). Due to ¼ Bradykinin its strategic location between circulating blood and ¼ Heparin sulfate the vessel wall the endothelium interacts with Thrombolytic factors Adhesion molecules neurohumoral cells and mediators, regulating in this ¼ Tissue-type plasminogen Leucocytes adhesion molecule way vascular contractility and cell composition. activator Intercellular adhesion molecule ¼ Stress and pulsating narrowing of the blood vessel Inhibitor I of the Blood cells adhesion molecules plasminogen activator walls are the most important stimuli for release of ¼ Thrombomodulin NO together with the release of systemic and local vasoactive substances.7 The main vasodilators released from endothelial cells include NO, bradykinin and prostacyclin. NO thelium and platelets aggregation. The endothelium is the most powerful endogenous vasodilator and it mediates the ability of the blood vessels to vary its seems to be responsible for the maintenance of basal architecture in response to haemodynamic changes. vascular tone.5,6,8 It is synthesized in the endo- Numerous works demonstrate that NO produced by thelium cells from L-arginine through the action of the endothelium is the main contributor to this NO synthetase.9 Additional properties of NO remodelling participating critically as a negative include inhibitory effects on migration of smooth regulator for the proliferation of vessels smooth muscle cells, adhesion of leucocytes to the endo- muscle in response to stimuli.10 Bradykinin is a potent vasodilator at the same time stimulating the release of NO and hyperpolariz- Table 1 Functions of the vascular endothelium ing factor derived from endothelium, both of which are vasodilatory substances.5 Bradykinin exerts its (1) Highly selective permeable barrier Regulation of plasma fluid, ions and macromolecules from and vasodilatory activity mainly through the release of to the vascular space. NO. Other effects of bradykinin are to promote the (2) Immunological, enzymatic and inflammatory function production of tissue-type plasminogen activator (t- Production of interleukine-I, which induces generation of T PA) supporting by this means the maintenance of cells. the fibrocytic balance. It also exhibits an antiaggreg- Antigen supplies to immunocompetent cells. ant effect upon the platelets through the release of Local production of angiotensin-converting enzyme (ACE). NO and prostacyclin. Promotion of production of adhesion molecules that participate in the inflammatory reaction. Apparently the inhibitors of the angiotensin-converting enzyme (ACE) act by accumulation of brady- (3) Detection of biochemical changes in blood and 11 maintenance of homeostasis kinin. The most important form of endothelium-

Recognition of variations of pH and oxygen and CO2 derived vasoconstrictor substances comprise angio- concentration participating in this way in cardiovascular tensin II and endothelin. Angiotensin II is a power- homeostasis. ful vasoconstrictor with various effects on blood (4) Autocrine function vessel structure and on vascular homeostasis Release of vasoactive substances, which regulate vascular tone: (Figure 1).12 Nitric oxide, prostacyclin Angiotensin II increases the production of type 1 Endothelin, thromboxane Angiotensin-I and angiotensin-II inhibitor of the plasminogen activator and the primary endogenous inhibitor of t-PA and promotes (5) Control of growth and cell proliferation vascular growth and in addition stimulating the gen- Induction of the production of vascular smooth muscle promotors. eration of different growth factors. Angiotensin II Induction of the production of vascular smooth muscle also elevates the response of platelets to aggregation inhibitors. against direct platelet agonists and stimulates the Induction of adhesion molecules for blood cells. production of endothelin, which is considered the (6) Haemostatic function most potent endogenous vasoconstrictor. Insurance of blood fluidity. Recently more attention is being given to the poss- Thromboresistant activity through anticoagulant, fibrinolytic ible role of another biologically active component of and platelet antiaggregation properties. Promotion of the production of procoagulant and anticoagulant the angiotensin system, angiotensin III, also called 2–8 substances: PGI2, endothelin I, fibronectin, tissue-type [des-Asp] or angiotensin. It is made by the cata- plasminogen activator and heparan. lytic action of aminopeptidase upon angiotensin II or through the action of ACE on angiotensin I.

Journal of Human Hypertension Endothelial dysfunction in arterial hypertension F Contreras et al S22

Figure 1 Effects of angiotensin on the regulation of arterial pressure. NA, noradrenaline.

Angiotensins III and II have qualitatively similar tension, pre-eclampsia, ischaemic cardiopathy, effects. Angiotensin III has almost the same action renal insufficiency, subarachnoid haemorrhage and as angiotensin II in the promotion of aldosterone brain ischaemia.15 secretion. However, angiotensin III possess only 10 The similarity of endothelin with neurotoxins to 25% of the power of angiotensin II to increase suggests that its action consists in the modulation of arterial pressure. Angiotensin-(1–7) an aminotermi- the ion channels. Its effects depend on Ca presence nal heptapeptide, is produced in different tissues. In and is not modified by cholinergic or serotoninergic blood vessels its production is the consequence of block. Today it is known that ET-1 promotes Ca the action of tissue endopeptidases upon angioten- uptake to the cells by two mechanisms: (1) direct Ca sin I and angiotensin II.13 In vascular smooth mobilization independent of dihydropyridines; and muscles it can be obtained from angiotensins I and (2) through the Ca channels. II through the action of metalloendopeptidases and The role that ET-1 plays in the regulation of vascu- propylendopeptidases. Evidence from a number of lar tone is beyond doubt. Nevertheless an intact animal studies suggests that angiotensin-(1–7) is a endothelium is required to observe any effect since vasodilator that may confer cardioprotective effects the actions of both prostacyclin and NO, stimulated by opposing the action of angiotensin II on growth by ET-1, must be added to antagonise endothelin and reactivity of blood vessels. Unlike angiotensin vasoconstrictor activity. All these mechanisms II angiotensin-(1–7) causes no vasoconstriction, together control vascular tone and blood flow in the aldosterone release, thirst or induction of norad- systemic or local environment according to its renergic neurotransmission. Its vasodilatory effect is needs. mediated by the production of endothelial NO and It is well known that ET-1 is stimulated by norad- bradykinin.14 renaline, thrombine, hypoxia, increased transmural Endothelin promotes the proliferation of smooth pressure and distension of the arteries. Insulin muscle cells and the secretion of extracellular stimulates the synthesis and discharge of ET-1 matrix, which contribute to the formation of atheros- which partially explains arterial hypertension by clerotic plaque. Endothelins are regulatory peptides hyperinsulinaemia and the existing connection distributed among many organic systems that pro- between insulin resistance and arterial pressure. duce powerful physiological effects. It is the most One of the fundamental points about the pathologi- potent known vasoconstrictor substance and from a cal function of ET-1 is its mitogenic effect, parti- pathological stand-point seems to be involved in cularly on the ateroma plaque.12 The normal endo- several diseases related to the vascular system such thelium functions in an inhibitory way maintaining as arterial hypertension (AHT), pulmonary hyper- the relaxation of vascular tone and inhibiting

Journal of Human Hypertension Endothelial dysfunction in arterial hypertension F Contreras et al S23 smooth muscle growth, adhesion, and aggregation of eases the vasodilator function is attenuated. In platelets and thrombosis. It is evident that any alter- advanced artheriosclerotic lesions the endothelium- ation of this inhibitory function of the endothelium dependent vasodilatation might be even abolished.19 can be followed by a vasoconstrictive response with There exist several grades and forms of endo- elevation of peripheral vascular resistance and thelial dysfunction: (1) damage of the Galphai pro- arterial pressure, stimulation of the growth of vascu- teins; (2) a decreased release of NO, prostacyclin and lar smooth muscle and increase of platelets or hyperpolarizing factor derived from endothelial adhesion and aggregation with ensuing thrombo- (EDHF); (3) increase of endoperoxidases discharge; genic effects. (4) increase in reactive oxygen species; (5) increase in the production of endothelin 1 (ET-1); and (6) decrease of smooth muscle sensitivity to NO, prosta- Endothelial dysfunction cyclin and/or EDHF. The term ‘endothelial dysfunction’ is recently being Bradykinin and angiotensin II levels within the used to identify general abnormalities of the func- vascular wall are controlled by ACE. ACE degrades tions that usually perform the endothelium. Endo- bradykinin and produces angiotensin II. Bradykinin thelial dysfunction is widely accepted as an early stimulates the endothelial cells to release vaso- event in the pathogenesis of cardiovascular diseases. dilatory substances. The activity of kinins holds up This observation is based on the signiﬁcance of the in spite of endothelial dysfunction except by severe endothelium in the preservation of cardiovascular arterial lesions. Angiotensin II might be partly health. Endothelial dysfunction and coronary responsible for endothelial dysfunction inasmuch as arterial disease are closely related to arterial hyper- it induces resistance to the vasodilator action from tension (AHT), hypercholesterolaemia, diabetes NO. For this reason if the production of angiotensin mellitus and tobacco smoking,16,17 which constitute II is arrested the direct and indirect vasoconstrictor risk factors predisposing the development of athero- effects of this peptide are blocked.20 sclerosis since they enforce endothelial dysfunction A decline in NO production could be ascribed to: and alteration of smooth muscle cells as well as (1) changes in intracellular availability of L-arginine; coagulation disturbances17 (Figure 2). Endothelial (2) a decrease in the NO synthetase activity; and (3) injury produces denuded endothelium areas, break- alteration of NO release mediated by receptors in age of the intima and necrosis of the smooth muscle response to pharmacological or laminar stress. Ris- cells. Exposure of the subendothelium and the ing of NO degradation derives from the increase of components of the media to the blood stream acti- free oxygen radicals generated in the endothelium vates the haemostatic system.18 and/or vascular smooth muscles.19 Vasodilator damage originated by endothelial dysfunction might be due to a decrease in NO pro- Vascular endothelium, arterial hypertension and duction or slower response to NO by the vessel arteriosclerosis smooth muscles.17 In the majority of vascular dis- The signiﬁcance of the vascular endothelium for the development of arterial hypertension (AHT) related

Figure 2 Factors enhancing endothelial dysfunction. Endothelial cells might modify NO levels by releasing more oxygen-free radicals.

Journal of Human Hypertension Endothelial dysfunction in arterial hypertension F Contreras et al S24 with blood vessel damage is nowadays widely stimulates the activity of adhesion molecules and accepted as well as the fact that AHT tends to favours leucocytes sticking to the endothelium, worsen the endothelial vasodilatory function.21–23 which leads to acute inflammatory response, pro- Hypertension occurs in association with morpho- liferation of smooth muscle cells and additional syn- logical and functional changes of the endothelium thesis of extracellular matrix contributing in this expressed partly by subendothelial fibrin accumu- way to the pathogenesis of cardiovascular dis- lation and infiltration of endothelial cells and eases.29 through modification of processes mediated by NO, Endothelial dysfunction is also present in differ- endothelin and cyclooxygenase products affecting ent conditions accepted as risk factors for arterio- the regulation of endothelium-dependent vascular sclerosis such as AHT, diabetes mellitus, tobacco tone. smoking and dislipidaemia (Figure 2). In AHT, ano- Patients suffering from AHT show impairment of malies have been reported in fibrinolysis, endo- endothelium-dependent vasodilatation associated thelial function, and glucose and lipid metabolism. with an anomalous function of the endothelial NO The results indicated that fibrinolytic alterations are system. According to different findings reactive oxy- linked with endothelial dysfunction and disorders gen species are also involved in the pathogenesis of of glucose and lipid metabolism. Treatment based hypertension and several connected disorders. As a on ACE inhibitors improves fibrinolysis and endo- consequence of alterations in the balance between thelial dysfunction.30 vasoconstrictor substances such as thromboxane With severe arterial hypertension high levels of and isoprostanes and vasodilators like NO, reactive hepatocyte growth factor (HGF) have been found. oxygen species contribute to endothelium-depen- The amounts of HGF—a member of endothelium- dent contractions and to the increase of peripheral specific growth factors—were more elevated when vascular resistance (Figure 2). Numerous oxygen- AHT was accompanied by systemic complications. free radicals act modifying essential biological mol- Nevertheless it diminishes significantly to normal ecules like lipids, proteins and DNA producing values as soon as hypertensive therapy has been changes in their function. Cytotoxic products and applied. HGF may then represent a new index for formation of fat-filled macrophages contribute to the the severity of AHT.31 development of atherosclerotic plaque. In addition, It is interesting to note that the endothelium- each peroxide radical can propagate itself many dependent lower vasodilatation present in hyperten- times, an event that, if it is not under control, might sive persons can be demonstrated using agonists like produce an extensive lipid peroxidation. acetylcholine and bradykinin, substances acting The formation of O2 in the vascular wall is asso- through different receptors and intracellular signals ciated with abnormal situations like hypercholester- pathways.32 This suggests that endothelial dysfunc- olaemia, although its metabolic pathway has not tion by hypertension should not be ascribed to been clearly identified. Furthermore its potential defects of the muscarine receptors. toxic role was deduced only because of the presence Much evidence indicate that the endothelium- of superoxide dismutase24 that works as an oxygen dependent lower vasodilatation, at least in some sweeper mechanism and is concentrated especially forms of hypertension, is not due solely to changes in the intima layer. For that reason antioxydant in NO mediated mechanisms. Endothelium-derived agents must be considered in AHT therapy.25 contraction factors produced in higher quantities Sodium plays also an important part on the patho- can participate too.33–35 However, in rats with spon- genesis of AHT, a major factor for cardiovascular taneous hypertension the low vasodilatory response disease. Studies of endothelium involvement in vas- to different agonists (serotonin, acetylcholine, cal- cular changes produced by salt-induced or salt cium ionophores) can be partially or completely sensitive AHT suggest that ET-1 acts as a local restored by inhibitors of the synthesis of prosta- mediator of vascular dysfunction and aortic glandins or by blocking prostaglandins H2 recep- hypertrophy. Antagonists of ET-1 receptors possess tors.35,36 The metabolism of arachidonic acid may be a crucial therapeutic potential by diminishing ET-1 probably altered, which increases the production of levels improving endothelial function and pre- vasoconstrictor prostaglandins. Similarly, in indi- venting structural changes caused by salt sensitive viduals with essential hypertension the lower vaso- AHT.25 dilatation in response to acetylcholine in forearm A potential role of ET-1 as mediator in vascular circulation is partially recovered with previous hypertrophy in response to angiotensin II has been indomethazine treatment, an inhibitor of prosta- demonstrated26 as well as the association of ET-1 glandins synthesis. with remodelling of the intima by arteriosclerosis as Obviously endothelial dysfunction is always a reaction to vessel damage.27 The inbalance present in hypertension, although it is not known if between NO and angiotensin II activities observed we are dealing with a primary phenomenon or the by endothelial dysfunction and the presence of cor- consequence of a higher arterial pressure. It appears onary disease risk factors causes oxydative stress, in established but not in early hypertension and can which derives from the excessive production of oxy- be reversed through antihypertensive drugs. There- gen-free radicals and the subsequent catabolism of fore, apparently in almost all animal hypertension NO. Angiotensin II-induced AHT exhibits an models, endothelial dysfunction is a consequence increase in the production of oxygen-free radicals of, and not a cause of the problem. promoting oxydative stress.28 The higher generation Given the fundamental role of endothelial dys- of oxygen-free radicals opposes the effects of NO, function as a central mechanism involved in many

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Journal of Human Hypertension