Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome

Endothelial dysfunction is a well established response to cardiovascular risk factors and precedes the development of atherosclerosis. Endothelial dysfunction is involved in lesion formation by the promotion of both the early and late mechanisms of atherosclerosis including up-regulation of adhesion molecules, increased chemokine secretion and leukocyte adherence, increased cell permeability, enhanced low-density lipoprotein oxidation, platelet activation, cytokine elaboration, and vascular smooth muscle cell proliferation and migration. Endothelial dysfunction is a term that covers diminished production/availability of nitric oxide and/or an imbalance in the relative contribution of endothelium-derived relaxing and contracting factors. Also, when cardiovascular risk factors are treated the endothelial dysfunction is reversed and it is an independent predictor of cardiac events. We review the literature concerning endothelial dysfunction in regard to its pathogenesis, treatment, and outcome.     

Endothelial effects of antihypertensive treatment: focus on irbesartan

The endothelium is characterized by a wide range of important homeostatic functions. It participates in the control of hemostasis, blood coagulation and fibrinolysis, platelet and leukocyte interactions with the vessel wall, regulation of vascular tone, and of blood pressure. Many crucial vasoactive endogenous compounds are produced by the endothelial cells to control the functions of vascular smooth muscle cells and of circulating blood cells. These complex systems determine a fine equilibrium which regulates the vascular tone. Impairments in endothelium-dependent vasodilation lead to the so called endothelial dysfunction. Endothelial dysfunction is then characterized by unbalanced concentrations of vasodilating and vasoconstricting factors, the most important being represented by nitric oxide (NO) and angiotensin II (AT II). High angiotensin-converting enzyme (ACE) activity leads to increased AT II generation, reduced NO levels with subsequent vasoconstriction. The net acute effect results in contraction of vascular smooth muscle cells and reduced lumen diameter. Furthermore, when increased ACE activity is chronically sustained, increase in growth, proliferation and differentiation of the vascular smooth muscle cells takes place; at the same time, a decrease in the anti-proliferative action by NO, a decrease in fibinolysis and an increase in platelets aggregation may be observed. AT II is then involved not only in the regulation of blood pressure, but also in vascular inflammation, permeability, smooth muscle cells remodelling, and oxidative stress which in turn lead to atherosclerosis and increased cardiovascular risk. Given the pivotal role exerted by AT II in contributing to alteration of endothelial function, treatment with ACE inhibitors or angiotensin receptor blockers (ARBs) may be of particular interest to restore a physiological activity of endothelial cells. In this view, the blockade of the renin-angiotensin system (RAS), has been shown to positively affect the endothelial function, beyond the antihypertensive action displayed by these compounds. In this review, attention has been specifically focused on an ARB, irbesartan, to examine its effects on endothelial function.     

Postprandial hyperglycemia on vascular endothelial function: mechanisms and consequences

Vascular endothelial dysfunction precedes atherosclerosis and contributes to cardiovascular disease (CVD), which accounts for one-third of all deaths in the United States. Chronic hyperglycemia, such as that associated with diabetes, is well known to impair vascular function. However, recent evidence demonstrates that acute or postprandial hyperglycemia (PPH) not only exacerbates vascular endothelial dysfunction in individuals with chronic hyperglycemia but also transiently impairs vascular function in healthy individuals. Postprandial hyperglycemia has been shown to better predict future CVD mortality compared with fasting glucose in both diabetic and normoglycemic individuals. Compelling evidence exists suggesting that PPH-mediated insults to the vascular endothelium contribute to CVD, especially in pathophysiologic conditions whereby vascular recovery is compromised. Although the mechanisms by which PPH induces vascular dysfunction is not fully understood, oxidative stress–mediated disruptions in nitric oxide homeostasis are implicated as key events leading to vascular dysfunction associated with PPH. This review aims to highlight the findings of clinical studies using functional indices of vascular function to demonstrate that PPH impairs vascular function. We will also discuss the evidence showing the central involvement of oxidative stress in dysregulating nitric oxide homeostasis and contributing to PPH-mediated vascular endothelial dysfunction. Lastly, this review will identify areas of knowledge that remain limited and will provide recommendations for future investigation to more fully define PPH as an important risk factor for CVD.     

Endothelial dysfunction

The endothelium is a major regulator of vascular tone, releasing vasoconstrictive (endothelin, cyclooxigenase-dependent factors, including prostanoids and oxygen free radicals) and vasodilating (endothelium--derived nitric oxid, endothelium--derived hyperpolarizing factor) mediators. These biologically active substances control not only the vascular tone but the vascular structure and permeability, coagulation and fibrinolysis, as well inflammatory response of the vascular wall. In endothelial dysfunction the balance in the endothelial production of vasodilating and vasoconstricting substances is altered resulting an apparent decrease in endothelium-dependent relaxations. Endothelial dysfunction is an important event in the pathogenesis of the early phase of atherosclerosis and hypertension. The testing and monitoring of endothelial dysfunction include tests of endothelium-dependent vasomotion, as well as circulating markers of endothelial damage. Further methods are needed to build up a panel of tests which measure the extent of endothelial dysfunction (= subclinical atherosclerosis), predict the subsequent risk and response to therapy.     

Prevention and preventive therapy of age-related macular degeneration through the beneficial effect of treatment of endothelial dysfunction

The beneficial effect achieved by the treatment of endothelial dysfunction in chronic cardiovascular diseases is already an evidence belonging to the basic treatment of the disease. Given the fact that the vascular system is uniform and consubstantial both physiologically, pathophysiologically and in terms of therapy, and that it plays a key role in age-related macular degeneration (AMD) - a disease leading to tragic loss of vision with its etiology and therapy being unknown -, endothelial dysfunction should be treated. The pleiotropic effects of ACE-inhibitors, AR-blockers and statins help to restitute the balance between vasodilators and vasoconstrictors in endothelial dysfunction caused by oxidative stress, the balance of growth factors and their inhibitors, pro- and anti-inflammatory substances and prothrombotic and fibrinolytic factors, inhibit the formation of oxidative stress and its harmful effects; while aspirin with its pleiotropic effects acting as an antiaggregation substance on platelets helps to set the endothelial layer back to its normal balance regarding its vasodilating, antithrombotic, anti-adhesive and anti-inflammatory functions. For the above reasons it is suggested that, as a part of long term primary and/or secondary prevention, the following groups of patients with AMD receive - taking into consideration all possible side effects - ACE-inhibitor and/or AR-blocker and statin and aspirin treatment: 1) those without maculopathy but being over the age of 50 and having risk factors inducing endothelial dysfunction; 2) those, who already developed AMD in one eye as a prevention in the second, unaffected eye; and 3) those patients who developed AMD in both eyes in order to ameliorate or merely slow the progression of the disease. Besides, it is advisory to inhibit AMD risk factors inducing oxidative stress with consecutive endothelial dysfunction.     

New possibilities in the pharmacologic prevention of age-related macular degeneration

The beneficial effect achieved by the treatment of endothelial dysfunction in chronic cardiovascular diseases is already an evidence belonging to the basic treatment of the disease. Given the fact that the vascular system is uniform and consubstantial both physiologically, pathophysiologically and in terms of therapy, and that it plays a key role in age-related macular degeneration (AMD)--a disease leading to tragic loss of vision with its etiology and therapy being unknown--endothelial dysfunction should be treated. The pleiotropic effects of ACE-inhibitors, AR-blockers and statins help to restitute the balance between vasodilators and vasoconstrictors in endothelial dysfunction caused by oxidative stress, the balance of growth factors and their inhibitors, pro- and anti-inflammatory substances and prothrombotic and fibrinolytic factors, inhibit the formation of oxidative stress and its harmful effects; while aspirin with its pleiotropic effects acting as an antiaggregation substance on platelets helps to set the endothelial layer back to its normal balance regarding its vasodilating, antithrombotic, antiadhesive and anti-inflammatory functions; trimetazidine as an adjuvant agent helps to normalize, to restore the disturbed metabolism of the retinal tissue functioning insufficiently, in the end. For the above reasons it is suggested that, as a part of long term primary and/or secondary prevention, the following groups of patients with AMD receive--taking into consideration all possible side effects--ACE-inhibitor and/or AR blocker and statin and aspirin treatment, and trimetazidine as adjuvant medicine 1. those without maculopathy but being above the age of 50 and having risk factors inducing endothelial dysfunction; 2. those, who already developed AMD in one eye as a prevention in the second, unaffected eye; and 3. those patients who developed AMD in both eyes in order to ameliorate or merely slow the progression of the disease. Besides, it is advisory to eliminate AMD risk factors inducing oxidative stress with consecutive endothelial dysfunction.     

Molecular mechanisms associating oxidative stress with endothelial dysfunction in the development of various vascular complications in diabetes mellitus

Endothelial dysfunction plays a key role in the pathogenesis of microangiopathy and macroangiopathy in type 2 diabetes mellitus. The endothelial dysfunction is induced by some cell metabolism disorders which are implicated in the pathogenesis of micro- and macroangiopathies through the principal mediation of oxidative stress. The discussion focuses preferentially on the recently found molecular mechanisms of free radical generation and on the endothelial disorders resulting from some free-radical-induced abnormalities in the intracellular signal pathways. We specify the molecular targets in the vascular complication therapy of diabetes on the basis of evidence of association between oxidative stress, metabolic abnormalities and endothelial dysfunction.     

Spermidine Supplementation Protects the Liver Endothelium from Liver Damage in Mice

Chronic liver diseases are multifactorial and the need to develop effective therapies is high. Recent studies have shown the potential of ameliorating liver disease progression through protection of the liver endothelium. Polyamine spermidine (SPD) is a caloric restriction mimetic with autophagy-enhancing properties capable of prolonging lifespan and with a proven beneficial effect in cardiovascular disease in mice and humans. We evaluated the use of dietary supplementation with SPD in two models of liver disease (CCl₄ and CDAAH diet). We analyzed the effect of SPD on endothelial dysfunction in vitro and in vivo. C57BL/6J mice were supplemented with SPD in the drinking water prior and concomitantly with CCl₄ and CDAAH treatments. Endothelial autophagy deficient (Atg7endo) mice were also evaluated. Liver tissue was used to evaluate the impact of SPD prophylaxis on liver damage, endothelial dysfunction, oxidative stress, mitochondrial status, inflammation and liver fibrosis. SPD improved the endothelial response to oxidative injury in vitro and improved the liver endothelial phenotype and protected against liver injury in vivo. SPD reduced the overall liver oxidative stress and improved mitochondrial fitness. The absence of benefits in the Atg7endo mice suggests an autophagy-dependent effect of SPD. This study suggests SPD diet supplementation in early phases of disease protects the liver endothelium from oxidative stress and may be an attractive approach to modify the chronic liver disease course and halt fibrosis progression.     

The Role of Obesity-Induced Perivascular Adipose Tissue (PVAT) Dysfunction in Vascular Homeostasis

Perivascular adipose tissue (PVAT) is an additional special type of adipose tissue surrounding blood vessels. Under physiological conditions, PVAT plays a significant role in regulation of vascular tone, intravascular thermoregulation, and vascular smooth muscle cell (VSMC) proliferation. PVAT is responsible for releasing adipocytes-derived relaxing factors (ADRF) and perivascular-derived relaxing factors (PDRF), which have anticontractile properties. Obesity induces increased oxidative stress, an inflammatory state, and hypoxia, which contribute to PVAT dysfunction. The exact mechanism of vascular dysfunction in obesity is still not well clarified; however, there are some pathways such as renin–angiotensin–aldosterone system (RAAS) disorders and PVAT-derived factor dysregulation, which are involved in hypertension and endothelial dysfunction development. Physical activity has a beneficial effect on PVAT function among obese patients by reducing the oxidative stress and inflammatory state. Diet, which is the second most beneficial non-invasive strategy in obesity treatment, may have a positive impact on PVAT-derived factors and may restore the balance in their concentration.     

Endothelial nitric oxide in diabetes mellitus: too much or not enough?

Vascular complications are the leading cause of increased mortality in patients with diabetes mellitus. Endothelial dysfunction, characterised by impaired endothelium-dependent vasoreactivity, is the first sign of blood vessel damage that precedes morphological changes of the vessel wall. With other factors altered bioavailability of nitric oxide, the most potent endothelium-derived vasodilator, contributes to the changes in vascular tone and integrity. In addition to the impairment of vascular reactivity and permeability, other anti-atherosclerotic functions of nitric oxide are also diminished, which may result in activated monocyte, leukocyte and platelet adhesion to the endothelium, increased platelet aggregation, lipoprotein influx to the subendothelial space and smooth muscle proliferation. Hyperglycaemia-induced increased oxidative stress and impairment of antioxidant defence are suggested to play a role in the pathomechanism of vascular damage, partly by influencing nitric oxide. Both in experimental and clinical Type 1 and Type 2 diabetes mellitus the apparently conflicting data of increased, unaltered or diminished nitric oxide action suggests a complex, time and localisation-dependent alteration of vascular function. The understanding of the mechanisms that lead to diabetic endothelial dysfunction and its early detection are necessary to establish appropriate intervention to prevent irreversible atherosclerotic vessel damage in patients with diabetes mellitus.     

Endothelial function in high risk cardiovascular patients

INTRODUCTION: Endothelial dysfunction is caused by risk factors, which have basic, and initial role in atherogenesis. During further progression it is still not known, whether is and how is endothelial dysfunction influenced by risk factors in the late phase of atherosclerosis and/or what kind of other factors play role in endothelial dysfunction. OBJECTIVES: Brachial artery flow mediated vasodilation was examined in 293 high risk patients (vascular 2. type diabetes patients/persons with + 2 risk factors). Relationship between endothelial function and risk factors, and risk stratifications were statistically examined to define the principal predictors of endothelial dysfunction. METHODS: 1. Examination of flow mediated vasodilation of brachial artery with ultrasound machine, 2. Risk factors evaluating, 3. Vascular examinations: physical, exercise test, Holter monitoring, CW Doppler, duplex scan 4. Risk stratification (10 year risk of fatal vascular events), 5. Statistical analysis (comparative and cohort). RESULTS: 1. Mean endothelial function of 293 high risk patients was reduced (105.1%). 2. Vascular disease plays principal role of the endothelial function in late phase atherosclerosis, because significantly decreases the brachial artery vasodilation (104.3% v. 108.3% p < 0.01) and significantly more (p < 0.0009) endothelial dysfunction can be found in patients with vascular disease than without. 3. Bad risk stratification plays principal role too, because there are significantly (p = 0.012) more endothelial dysfunction in high risk patients, than with better risk stratification. 4. Lipid-, glucose-metabolic alterations, hypertension, age and smoking (all: p = NS) have not already any role in endothelial dysfunction in late phase atherosclerosis. CONCLUSIONS: Role of risk factors in initial atherogenesis is scientific evidence, but the role of these factors can not be proved later, when endothelial dysfunction already evolved. In this phase of atherosclerosis the vascular disease and the bed risk stratification have principal role, because they can cause significant more reduction of already reduced endothelial function. Further studies necessary to determine, whether this statistically proved relationship have, or have not any clinical relevance.     

Asymmetrical dimethylarginine regulates endothelial function in methionine-induced but not in chronic homocystinemia in humans: effect of oxidative stress and proinflammatory cytokines

BACKGROUND: Homocystinemia is a metabolic abnormality associated with endothelial dysfunction and increased cardiovascular disease risk. The underlying mechanisms of these effects, however, are obscure. OBJECTIVE: We examined the effect of asymmetrical dimethylarginine (ADMA) on endothelial dysfunction in methionine-induced and chronic homocystinemia and evaluated the regulatory role of oxidative stress and proinflammatory cytokines on the release of ADMA. DESIGN: In this double-blind, placebo-controlled parallel group study, 30 subjects of both sexes (15 with homocystinemia and 15 healthy controls) underwent methionine loading, with simultaneous administration of a combination of vitamin C (2 g) plus alpha-tocopherol (800 IU) or placebo. Endothelial function in forearm resistance vessels and concentrations of ADMA, oxidized LDL, and proinflammatory cytokines were determined at baseline and 4 h after methionine loading. RESULTS: Both chronic and methionine-induced homocystinemia were associated with increased oxidized LDL (P < 0.01), higher expression of the proinflammatory cytokine interleukin 6 (P < 0.05), and endothelial dysfunction (P < 0.01). Although ADMA rapidly increased in acute homocystinemia (P < 0.01) and was correlated with forearm hyperemic response at 4 h after methionine loading (r = -0.722, P = 0.0001), it was not higher in subjects with high versus low fasting homocysteine. High-dose antioxidant treatment prevented methionine-induced elevation of oxidized LDL and interleukin 6 but failed to prevent the increase in ADMA or endothelial dysfunction. CONCLUSIONS: Both chronic and methionine-induced homocystinemia are characterized by increased oxidative stress and proinflammatory cytokines, which may contribute to the development of endothelial dysfunction. However, the ADMA pathway is activated only in acute homocystinemia by mechanisms not mediated by oxidized LDL or proinflammatory stimuli.     

Instrumental methods for evaluation of endothelial function

Endothelial dysfunction is a systemic disorder with a key role in the pathogenesis of atherosclerosis and its complications. Current evidence suggests that endothelial status is not determined solely by the individual risk factor burden but is rather regarded as an integrated index of all atherogenic and atheroprotective factors present in an individual, including known as well as yet-unknown variables and genetic predisposition. Endothelial dysfunction reflects a vascular phenotype prone to atherogenesis and may therefore serve as a marker of the inherent atherosclerotic risk in an individual. Recent advances in the understanding of pathophysiology of early atherosclerosis have opened up new opportunities for development of methods for assessment of the earliest changes in the vessel wall. During the last decade some noninvasive techniques have been introduced in clinical practice among which the ultrasound assessment of flow-mediated vasodilation of the brachial artery is the most widely used. These stimuli induce the endothelium to release nitric oxide which causes vasodilation that can be visualized and measured as an index of the vasomotor activity. This technique is attractive because it is non-invasive, accessible and reproducible in everyday clinical practice.     

The role and clinical importance of nitric oxide-endothelin system in hypertension

This review summarises the role of the endothelium in the regulation of the vascular tone, emphasizes the importance of nitric oxide and endothelin at the vasodilator and vasoconstrictor physiological processes. Mainly, the nitric oxide is responsible for the basal tone of the vasculature, but plenty of modifying factors (endothelin, angiotensin-II, prostacyclin) have also important effects. Endothelial dysfunction observable in hypertension, which characterised by disorder of the endothelium-dependent relaxation, and predominance of the vasoconstrictor processes. Disorder of synthesis, decreased biological activity and increased degradation of the nitric oxide could play a role in the fall of the basal vasodilator tone, as well as other factors influencing the production of nitric oxide. Due to a relaxation disorder, the vasoconstrictor endothelin come to the front, following morphological changes of the vessels, afterwards. Endothelial dysfunction of the medium size arteries lead to thickening of the intima, what can follow by non-invasive measurements at the common carotid arteries. It is unambiguous in hypertensive patients that augmenting the tone of the resistance vessels, the peripheral vascular tone increases. It is proved in hypertensive adults that damaged function of the cerebral arterioles results in decrease of the vasoreactivity following a hypo- or hypercapnic stimuli. The imbalance of the nitric oxide-endothelin system is not only a process what helps to partly explain the pathophysiology of hypertension, but also a therapeutic aim preventing the process of atherosclerosis.     

Proatherogenic changes induced by hemodialysis; probably a result of bio-incompatibility

Chronic haemodialysis patients have a disproportionately high risk for developing cardiovascular disease, which can only in part be explained by known risk factors such as dyslipidaemia, hypertension, hyperhomocysteinemia, diabetes mellitus and chronic volume expansion. A possible cause is that the haemodialysis treatment itself contributes to the accelerated atherosclerosis, observed in these patients. Nowadays, atherosclerosis is considered an inflammatory process, mediated by a dysfunction of the vascular endothelium. As a result, blood cells adhere to the vascular surface and release a variety of vasoactive mediators, cytokines, growth factors and free radicals. Due to the contact between blood and dialyzer, humoral systems and cellular elements are stimulated, and this may be viewed as an inflammatory reaction. As a consequence of this, the vascular surface of haemodialysis patients is repeatedly exposed to the influences of cytokines, coagulation products, vasoactive mediators, stimulated leukocytes and thrombocytes, and oxidative stress. It is therefore conceivable that the haemodialysis treatment itself enhances the greatly increased cardiovascular risk in chronic haemodialysis patients.     

Inflammation and cardiovascular disease

Cardiovascular disease (CVD) has been associated with the so-called traditional risk factors, such as hypertension, hypercholesterolemia and cigarette smoking. Chronic inflammation, exemplified by elevated high sensitivity C-reactive protein, has been added to these risk factors for CVD as non-traditional risk factor. There are two aspects in this association. The first is whether inflammation plays a pathogenic role in traditional risk factors-mediated CVD or it is just an epiphenomenon. The second is whether chronic inflammation caused by an inflammatory disease has any impact on CVD. Accumulated data have shown that inflammation has a central and inciting role in the development of atherosclerosis leading to increased CVD risk. How inflammation contributes to CVD is a topic of continuous research where mechanisms involving both innate and adaptive immune pathways are involved. Endothelial dysfunction, oxidative stress in vascular endothelial cells, macrophage accumulation, formation of inflammasome, production of tumor necrosis factor (TNF)-a, IL-1 and IL-6 characterize the inflammatory process leading to atherogenesis. Recently clonal hematopoiesis of indeterminate potential represents a surprising and novel mechanism underlying atherogenesis. Data from chronic rheumatic inflammatory diseases exemplify the complexity of mechanisms leading to increased CVD, while they also provide evidence that anti-inflammatory biologic drugs, such as anti-TNF and anti-IL6 agents, could control atherogenesis and ameliorate CVD risk. Recent groundbreaking work using biologic anti-IL-1b therapy to treat men and women who have had a prior heart attack provides the best proof of the pathogenic contribution of inflammation in the development of CVD.     

内皮功能障碍、氧化应激与心肌缺血再灌注损伤

导致缺血再灌注损伤的机制是多方面的:氧化应激、细胞内钙超载、中性粒细胞活化、血管内皮细胞功能障碍、能量代谢障碍及心肌细胞凋亡等.内皮功能失调是再灌注损伤病理发生的关键.氧衍生自由基明显增加是缺血-再灌注损伤发生的重要机制之一.现就血管内皮细胞功能障碍及氧化应激在心肌缺血再灌注损伤中的作用机制作一综述.