Arq Bras Cardiol Caramori Updateand Zago volume 75, (nº 2), 2000 Endothelial dysfunction and coronary artery disease Endothelial Dysfunction and Coronary Artery Disease Paulo R. A. Caramori, Alcides J. Zago Porto Alegre, RS - Brazil For several decades, the vascular endothelium was smooth muscle cells. In contrast, endothelial dysfunction ap- considered a unicellular layer acting as a semipermeable pears to play a pathogenic role in the initial development of membrane between the blood and the interstitium. Recently, atherosclerosis 7-9 and of unstable coronary syndromes 10, it has been demonstrated that the endothelium performs a being associated with atherosclerotic disease risk factors 11-18, large range of important biological functions, participating and being present even before vascular involvement be- in several metabolic and regulatory pathways. Along with comes evident 6,19-21. long-known specialized functions like gaseous exchange in Recent clinical studies have demonstrated that some the pulmonary circulation and phagocytosis in the hepatic drugs well known to reduce the incidence of cardiovascular and splenic circulation, the vascular endothelium performs events, improve endothelial function 22-25. On the other universal roles in the circulation that include participation in hand, clinical interventions like the continuous administra- thrombosis and thrombolytic control, vascular growth, tion of organic nitrates and percutaneous coronary inter- platelet and leukocyte interactions with the vascular wall, ventions may be associated with adverse effects on the and vasomotor tone. vascular endothelium. In the present article, we will discuss The study of endothelium-dependent vasomotor vascular endothelial function versus dysfunction, and reactivity has produced over the years, scientific evidence their impact on cardiovascular disease, in particular atheros- fundamental for the understanding of the endothelium’s clerosis. role in physiological and pathological situations. In 1977, Moncada et al, published the first report indicating that the The endothelium in cardiovascular homeostasis - endothelium plays a central role in the control of vascular Vascular endothelium may be considered a dynamic, hetero- tone via the production of vasoactive substances 1. In 1980, geneous organ, having secretory, synthesizing, metabolic, Furchgott and Zawadzki 2 demonstrated in an experimental and immunological functions, vital to human beings 26. The preparation of the rabbit aorta, the obligatory role played by endothelium regulates the flow of nutrient substances, of endothelial cells in vascular relaxation in response to effec- various biologically active molecules, and of blood cells tors like acetylcholine, and postulated the existence of a through the entire human body. It is selectively permeable, vascular relaxing factor derived from the endothelium. In possessing various cell membrane receptors for molecules 1987, two research groups, lead by Ignarro et al 3, and by that include proteins (growth factors, coagulation, and Palmer et al 4, demonstrated that the relaxing factor derived anticoagulation proteins), lipid-transporting particles from the endothelium was nitric oxide, an odorless gas until (LDL), metabolites (nitric oxide, serotonin), and hormones then considered as a mere pollutant. (endothelin-1). The endothelium plays a central role in the Endothelial dysfunction was first characterized in hu- regulation of vascular tone and blood flow by the secretion mans in 1986 by Ludmer et al, 5 who demonstrated that athe- and capture of paracrine vasoactive substances, contrac- rosclerotic coronary arteries contracted in response to in- ting or dilating specific vascular beds in response to tracoronary infusion of acetylcholine, while normal corona- various stimuli. ries showed dilatation. In 1992, endothelial dysfunction was The endothelium also possesses important anticoa- documented by Celermajer et al 6 in children and otherwise gulant, antiplatelet, and fibrinolytic actions. Endothelial healthy young adults with risk factors for atherosclerosis. cells are the largest sites of reactions involving thrombin 27. Under physiological conditions, the endothelium Some of the stimuli that activate platelets (adenosine di- keeps a reduced vasomotor tone, prevents leukocyte and phosphate and thrombin) also stimulate the release of platelet adhesion, and inhibits the proliferation of vascular prostacyclin by the endothelium, inhibiting platelet aggre- gation 1,28. In response to stimuli like noradrenaline, vaso- pressin, thrombin, and vascular stasis, endothelial cells se- crete tissue plasminogen activator 29, a potent thrombolytic agent with wide clinical application, thus providing a Hospital das Clínicas da Universidade Federal do Rio Grande do Sul - Porto Alegre defense against uncontrolled coagulation. Other hemosta- Mailing address: Paulo R. A. Caramori – Rua Ramiro Barcelos, 2350 – S/2059 - 90035-003 - Porto Alegre, RS - Brazil tic factors secreted by the endothelium, include plasmino- gen activating factor (PAI-1) inhibitor, von Willebrand 173 Caramori and Zago Arq Bras Cardiol Endothelial dysfunction and coronary artery disease volume 75, (nº 2), 2000 factor, and thrombomodulin. When stimulated by certain In the presence of a normal endothelium, the release of physical or chemical factors, the endothelial cell undergoes nitric oxide in response to catecholamines counteracts alpha- phenotypical modifications that determine its transforma- adrenergic vasoconstrictor effects. In contrast, when the tion into a thrombogenic surface. The dynamic equilibrium endothelium is dysfunctional, an increase in coronary va- existing between these two states often permits the endo- soconstriction in response to adrenergic stimuli occurs 36,37. thelial cell to return to its basal state, once the thrombogenic The increased synthesis of nitric oxide consequent to shear stimulus has ceased. stress, contributes to the flow-mediated phenomenon of Injury or activation in response to various pathologi- vasodilatation that is an important auto-regulatory physio- cal factors leads to modifications of the endothelial cell’s re- logical mechanism 38. The production of nitric oxide can be gulatory functions. The endothelium becomes incapable of blocked in vivo by analogues of L-arginine, like NG– maintaining vascular homeostasis. This characterizes a monomethyl-L-arginine (L-NMMA). Such blockade has condition of endothelial dysfunction, which can be defined been considerably useful for the study of the role of nitric as an imbalance between relaxing and contracting factors, oxide in physiological and pathological situations. The between procoagulant and anticoagulant mediators, or infusion of L-NMMA in the brachial human circulation between stimulants and inhibitors of cell growth and proli- leads to an increase in vascular peripheral resistance, and feration, respectively 30. intravenous infusion causes an increase in systemic arterial pressure. These findings indicate that the vasculature is in Endothelial vasomotor function - The endothelium a constant state of vasodilatation due to the continuous plays a fundamental role in the regulation of vasomotor tone release of nitric oxide (fig. 1). via the synthesis and release of vasodilator substancesni- tric oxide, prostacyclin, and the endothelium-derived hyper- In addition to the modulation of vasomotor tone, polarizing factor, as well as by the liberation of vasocons- endothelial cell-derived nitric oxide has several important trictor substances like endothelin-1 and platelet-activating vascular effects. Nitric oxide inhibits adhesion, activation, 39 factor. Nitric oxide is probably the main mediator of va- and platelet aggregation and promotes platelet deaggre- somotor tone in physiological situations, small amounts gation, in part by a cGMP-dependent mechanism. Nitric oxide being continuously secreted by the endothelial cells 4,31 to produced in response to thrombin inhibits platelets and mo- maintain a reduced arterial tone in the systemic and pulmo- dulates blood coagulation. Nitric oxide derived from the endo- nary circulations 32. The vasodilator activity of nitric oxide is thelium also inhibits leukocyte adhesion to the endothelium due to its interaction with the iron atom of the heme 40,41, migration 42, and proliferation 43 of vascular smooth prosthetic group of guanylate cyclase, causing its activa- muscle cells and stimulates the migration and proliferation tion and increasing the intracellular levels of cyclic guanidi- of endothelial cells 44. ne monophosphate (cGMP), 33. In smooth muscle cells, this The contribution of endothelial cells to the regulation decreases intracellular calcium concentration, causing vas- of vasomotor tone involves the production of other vasodi- cular relaxation 34. lator compounds like prostacyclin and the endothelium-de- Nitric oxide is a free radical produced by the oxidation rived hyperpolarizing factor. Prostacyclin is synthesized of L-arginine to L-citrulline, via nitric oxide synthetase, an from arachidonic acid by cyclo-oxygenase 1, being rapidly 35 enzyme that has at least three isoforms . Nitric oxide produced and released from endothelial cells 45 in response synthetase type III is a constitutive enzyme of the endothe- to humoral and hemodynamic factors. It interacts synergi- lial cell, which continuously produces small amounts of cally with nitric oxide, causing vasodilatation and inhibition nitric oxide. In contrast to other vasomotor agents