Endothelial Function
2011; Lippincott Williams & Wilkins; Volume: 124; Issue: 25 Linguagem: Inglês
10.1161/circulationaha.111.078824
ISSN1524-4539
Autores Tópico(s)Thermoregulation and physiological responses
ResumoHomeCirculationVol. 124, No. 25Endothelial Function Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBEndothelial Function Joseph A. Vita Joseph A. VitaJoseph A. Vita From the Evans Department of Medicine and the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA. Originally published20 Dec 2011https://doi.org/10.1161/CIRCULATIONAHA.111.078824Circulation. 2011;124:e906–e912The endothelium regulates vascular tone, platelet activity, leukocyte adhesion, and angiogenesis by producing nitric oxide and other regulatory factors. Risk factors decrease nitric oxide bioavailability and induce a proinflammatory endothelial phenotype that promotes atherosclerosis.1,2 In human subjects, endothelial dysfunction is associated with risk factors,3–5 correlates with disease progression,6 and predicts cardiovascular events.7–13 Risk reduction therapies improve endothelial function, and failure of the endothelium to respond is associated with higher risk.14 Thus, there is strong clinical evidence that endothelial dysfunction contributes to the pathogenesis of cardiovascular disease.In the past several years, experimental and clinical studies have provided new information about the mechanisms and clinical relevance of specific aspects of endothelial function. The purpose of this review is to summarize recent articles from Circulation that have advanced this field.Mechanisms of Endothelial Dysfunction: Experimental ModelsLoss of nitric oxide bioavailability (decreased synthesis or increased degradation) is a key manifestation of endothelial dysfunction that contributes to the pathogenesis and clinical expression of atherosclerosis. Endogenous inhibitors of endothelial nitric oxide synthase (eNOS), including asymmetrical dimethyl arginine, are elevated, and contribute to endothelial dysfunction in diabetes mellitus, renal failure, and other pathological states.15 Asymmetrical dimethyl arginine is metabolized by dimethylarginine dimethylaminohydrolase-1 (DDAH1), and using an endothelium-specific knockout mouse model, Hu and colleagues16 demonstrated that endothelial function is importantly regulated by endothelial DDAH1. Interestingly, the DDAH1-deficient mice were hypertensive, suggesting that the vascular endothelium is involved in blood pressure regulation. Consistent with this idea, smooth muscle cell–specific deletion of guanylyl cyclase, which is the primary target of nitric oxide,17 is also sufficient to produce hypertension in a mouse model.18It is well recognized that the incidence of cardiovascular events varies by time of day and the season of the year,19–21 and there is growing interest in the genes that regulate circadian rhythms.22 A recent study suggests that such genes influence vascular function. Anea and colleagues23 observed that genetic deletion of Bmal1 and Clock in mice impaired vasodilation and eNOS signaling and induced pathological arterial remodeling responses to low blood flow. Deletion of these clock genes also increased expression of prothrombotic factors by the endothelium. These results might be relevant to circadian patterns of cardiovascular events. They also raise the possibility that disruption of the biological clock in clinical situations such as sleep deprivation or jet lag might promote cardiovascular disease.22Another potential mechanism of endothelial dysfunction is alteration of the signaling mechanisms involved in eNOS activation. One relevant stimulus for eNOS activation is increased local levels of ADP. da Silva and colleagues24 showed that eNOS activation by ADP and other purinergic nucleotides is dependent on protein kinase Cδ and phosphorylation of eNOS. Interestingly, the effect did not depend on other kinases known to phosphorylate and activate eNOS, including Akt and AMP-dependent protein kinase (AMP kinase). ADP and other purine nucleotides are known to induce dilation by direct effects on vascular smooth muscle. This work demonstrates that they also induce endothelium-dependent dilation and identifies another signaling mechanism for eNOS activation that may be relevant to pathological states, including ischemia.Endothelial dysfunction is a prominent feature of metabolic diseases, including type 2 diabetes mellitus and obesity.25 A recent study suggests that aberrant endoplasmic reticulum (ER) stress may be important in these settings.26 In addition to its role in lipid synthesis and protein folding, the ER contributes to cell signaling. Activation of the ER stress response has been linked to inflammatory activation and atherosclerosis in a variety of cell types.27 Dong and colleagues26 completed a study showing that AMP kinase suppresses ER stress in endothelial cells. This effect was mediated in part through regulation of sarcoendoplasmic reticulum calcium ATPase and calcium homeostasis. Deficiency of AMP kinase promotes ER stress. Furthermore, an intervention that reduces ER stress reduced atherosclerotic lesion development in AMP kinase–deficient and hyperlipidemic mice. AMP kinase is recognized as a key regulator of cellular energy status that has favorable effects on eNOS activity, insulin sensitivity, and mitochondrial function in a variety of cell types, including vascular cells, skeletal muscle cells, and myocytes.28–31 This study provides further insight into the mechanisms accounting for the vascular benefits of interventions that activate AMP kinase, including calorie restriction and exercise.Another factor that regulates eNOS activity in the setting of metabolic disease is adropin, which was recently recognized to be an important regulator of energy homeostasis and insulin sensitivity that is produced in liver and brain.32 Lovren and colleagues33 demonstrated that adropin is expressed in endothelial cells and improves angiogenesis-related responses via activation of Akt, eNOS, and extracellular signal regulated kinase 1/2. Like adiponectin and leptin, adropin may be an endocrine factor that influences both insulin resistance and endothelial functions such as vasodilation and angiogenesis.34,35Aging is associated with endothelial dysfunction, and several recent studies provide insight into the associated mechanisms. Menghini and colleagues36 provided evidence that microRNA 217 is upregulated in aging and atherosclerosis, induces a senescence-like phenotype, and impairs angiogenic activity in cultured endothelial cells. This effect is mediated via downregulation of Sirt1, an NAD-dependent deacetylase that modifies gene expression, leading to altered endothelial signaling and decreased eNOS activity. Another regulator of gene expression in endothelial cells is histone deacetylase 3. Zampetaki and colleagues37 demonstrated that histone deacetylase 3 plays an important role in endothelial survival under conditions of altered shear stress that may relate to the pathogenesis of atherosclerosis.An important consequence of endothelial dysfunction with relevance for atherosclerosis and other disease states is altered function of gap junction proteins, leading to a loss of cell-to-cell communication and increased vascular permeability.33,38–40 Connexin40 is an endothelial gap junction protein with reduced expression in atherosclerosis. Chadjichristos and colleagues examined the effects of endothelial-specific deletion of connexin40 in mice fed a high-cholesterol diet.38 They observed accelerated development of atherosclerosis in the connexin40-null mice and increased expression of vascular cell adhesion molecule-1 and monocyte infiltration into the intima. Endothelial deletion of connexin40 also promoted inflammatory cell infiltration by altering cell-to-cell communication and decreasing endothelial expression of CD73, an ectoenzyme that hydrolyzes adenine nucleotides to adenosine, which has antiinflammatory properties. This study highlights the relevance of gap junction proteins for endothelial activation and atherogenesis.Although considerable attention has been paid to decreased bioavailability of nitric oxide as a primary cause of endothelial dysfunction, recent studies have focused on other endothelium-dependent vasodilators, including endothelium-derived hyperpolarizing factor (EOHF), which remains incompletely characterized. Brahler and colleagues41 provided evidence that the endothelial calcium-activity potassium channels SK3 and IK1 contribute to endothelium-derived hyperpolarizing factor–mediated vasodilator responses and that genetic deletion of these channels causes hypertension in a mouse model. Carbon monoxide is another endothelium-derived vasodilator that may be produced in a compensatory fashion in pathological states associated with reduced nitric oxide bioavailability.42,43 Wegiel and colleagues44 demonstrated that carbon monoxide prevents proliferation of vascular smooth muscle cells and promotes endothelial repair in an eNOS-dependent manner after vascular injury.According to the conventional view, endothelial cells influence cells in the arterial wall in a unidirectional manner. An interesting study by Balcells and colleagues45 provided further evidence for bidirectional signaling between endothelial and vascular smooth muscle cells. They studied the responses of endothelial cells to laminar flow when cultured in a model artery system alone or on top of a layer of vascular smooth muscle cells. They observed that flow-mediated activation of mammalian target of rapamycin (mTOR) signaling in endothelial cells was blunted by the presence of vascular smooth muscle cells and that the presence of endothelial cells blunted growth factor–induced activation of mTOR in vascular smooth muscle cells. Furthermore, coculture influenced the responses to a sirolimus-analog mTOR inhibitor. mTOR signaling is important for smooth muscle proliferation and reendothelialization after arterial injury, and mTOR inhibitors are used clinically on drug-eluting stents. Thus, these findings may have important implications for the biology of in-stent restenosis and late stent thrombosis. Given current interest in novel stent design,46 these findings emphasize the limitations of single-cell culture systems as models for study of the relevant biology.Mechanisms of Endothelial Dysfunction: Human StudiesSeveral recent studies have provided insight into the mechanisms of endothelial dysfunction in humans. One novel approach is the study of patients with polymorphisms or mutations of genes that might play a pathogenic role.47–50 Such studies provide a human parallel for knockout mouse studies. For example, Antoniades and colleagues47 examined how homocysteine metabolism may affect the endothelium and promote cardiovascular disease. They examined tissue and plasma homocysteine and 5-methyltetrahydrofolate (5-MTHF) levels in saphenous veins and internal mammary arteries obtained during bypass surgery from patients with polymorphisms of 5-MTHF reductase, which influences tissue levels of 5-MTHF. They observed that higher tissue 5-MTHF levels correlated with endothelium-dependent vasodilation and lower superoxide production in the isolated vascular tissue. Plasma and tissue homocysteine levels did not relate to vascular function.Using the same approach, 2 groups of investigators examined mutations in genes for subunits of NADPH oxidase and the consequences for endothelial function in humans.48,49 Chronic granulomatous disease is an inherited condition caused by detects in NADPH oxidase that lead to impaired immune function and chronic susceptibility to infection. NAPDH oxidase has also been implicated in experimental studies to be a major source of reactive oxygen species that contributes to endothelial dysfunction in a variety of disease states, including diabetes mellitus, hypertension, and ischemia reperfusion injury. Violi and colleagues49 observed that patients with chronic granulomatous disease have decreased activity of the NADPH subunit gp91phox, better endothelial function, and decreased markers of oxidative stress compared with healthy control subjects. Conversely, obese patients displayed higher gp91phox activity, impaired endothelial function, and increased markers of oxidative stress. Loukogeorgakis and colleagues48 observed that patients with chronic granulomatous disease are protected against ischemia/reperfusion-induced endothelial dysfunction assessed by brachial artery flow-mediated dilation. This study contributes to the growing body of evidence that NADPH oxidase activity contributes to endothelial dysfunction in humans and may be a target for therapy.51–55Chronic kidney disease is another pathological state associated with atherosclerotic vascular disease and endothelial dysfunction.56–59 Chung and colleagues60 showed that vascular dysfunction and arterial stiffness were related to upregulation of matrix metalloproteinase-2 in arterial tissue collected from patients with chronic kidney disease. Perticone and colleagues showed that impaired endothelial function assessed by intra-arterial acetylcholine infusion was associated with more rapid decline in glomerular filtration rate in patients with untreated hypertension and normal renal function at baseline.60a These findings raise the possibility that endothelial dysfunction might contribute to the pathogenesis of impaired renal function in patients with hypertension. Furthermore, interventions that protect the endothelium might prevent deterioration of renal function.Air pollution is another risk factor linked to cardiovascular disease in recent studies.61–63 Several studies have linked air pollution to endothelial dysfunction.64,65 In a mouse model, air pollution induced insulin resistance and endothelial dysfunction.66 This effect was attributable to increased adipose tissue inflammation, which has been linked to the pathogenesis of diabetes mellitus.67,68 These findings provide an example of how study of endothelial function may identify novel risk factors and provide insight into mechanisms of disease in humans.61–63,69–72Recent work suggests that endothelial health is determined by the availability of bone marrow–derived endothelial progenitor cells, which contribute to endothelial repair and angiogenesis.44,73–78 Bone marrow–derived cells may also be precursors for the endothelial lining of lymphatics.79 Cheng and colleagues80 provided support for the idea that impaired endothelial progenitor cell availability might contribute to atherosclerosis in humans. They observed that circulating endothelial progenitor cells, defined as colony-forming units, correlated inversely with the presence of coronary artery calcification and abdominal aortic calcification, markers of subclinical atherosclerosis. However, considerable controversy remains about the potential role of bone marrow–derived endothelial cells as promoters or inhibitors of the atherosclerotic process.81–85Effects of Interventions on Endothelial FunctionEndothelial vasodilator function has potential as a surrogate marker for the study of interventions to promote cardiovascular health. There is current interest in the pleiotropic effects of statins and the question of the whether different classes of cholesterol-lowering drug have different effects on the vasculature.86–88 Liu and colleagues89 completed a clinical trial in 60 patients with dyslipidemia to compare the effects of higher-dose statin (simvastatin 40 mg) and the combination of a lower-dose statin (10 mg) plus ezetimibe, which produce equivalent reductions in low-density lipoprotein cholesterol. They examined the effects on brachial artery flow-mediated dilation and on the activity of rho-associated coiled-coil protein kinase (ROCK) in leukocytes. The observed equivalent reductions in cholesterol and C-reactive protein levels, but only the 40-mg simvastatin group demonstrated improved endothelial function and reduced rho-associated coiled-coil protein kinase activity. These findings suggest that statin therapy in humans has benefits beyond cholesterol lowering, although the concept remains controversial. Clinical trials examining cardiovascular events are required to settle the issue.89–92 In addition to low-density lipoprotein, therapy that modulates high-density lipoprotein cholesterol may also have favorable effects on the endothelium.53There is great interest in the effects of lifestyle and diet on cardiovascular disease. Endothelial function may have utility as a surrogate end point for study of this issue, given the difficulty and expense of dietary studies that examine effects on cardiovascular events. McCall and colleagues93 tested the effects of a diet rich in fruit and vegetables on endothelial function as measured by the blood flow responses to the endothelium-dependent vasodilator acetylcholine in patients with hypertension. They demonstrated graded improvements in the acetylcholine response with increasing intake of fruits and vegetables. These findings are consistent with the growing evidence that flavonoid-containing foods and beverages have favorable effects on the vascular endothelium and cardiovascular risk.94,95It is well accepted that increased physical activity and an active lifestyle reduce cardiovascular risk, although the optimal type of exercise for cardiovascular benefit remains controversial.96–100 An interesting study by Vona and colleagues101 examined the effects of different types of exercise training on flow-mediated dilation and plasma von Willebrand factor. They observed equivalent and marked improvements in endothelial function after aerobic, resistance, and combined aerobic/resistance training for 4 weeks compared with control.A number of studies have investigated the mechanisms accounting for the benefits of exercise on endothelial function. For example, an experimental study by Werner and colleagues102 showed that exercise stabilizes telomeres and reduces apoptosis in the vascular wall. The benefits of exercise may also result from increased blood flow and improved shear stress at the endothelial surface. Pathological levels of shear stress, particularly low shear stress and disordered shear stress at branch points in the arterial tree, may promote alterations in endothelial gene expression and function to promote atherosclerosis.37,103,104 A variety of emerging noninvasive methods, including magnetic resonance imaging, allow the study of the relations between shear stress and atherogenesis.104 Another benefit of exercise on vascular health relates to increased production of circulating endothelial progenitor cells, which, as discussed above, are important for endothelial repair and angiogenesis.105The importance of inflammation for cardiovascular disease is well recognized, and there currently is great interest in the possible benefits of antiinflammatory drugs on vascular function. Pierce and colleagues54 demonstrated that treatment of overweight/obese patients with salsalate improved brachial artery flow-mediated dilation. Interestingly, this intervention also reduced total and nuclear expression of nuclear factor-κB in endothelial cells collected from patients before and after the intervention. Endothelial activation, as reflected by increased expression of nuclear factor-κB, accumulation of oxidatively modified proteins, and decreased expression and activity of eNOS, was also observed in endothelial cells isolated from patients with obstructive sleep apnea.106,107 Emerging methodology, including positron emission tomography scanning, may allow noninvasive monitoring of vascular inflammation in the setting of metabolic disease.108 The link between obesity and vascular dysfunction is emphasized by the observation that weight loss and improvement in obesity-associated risk factors were associated with significant changes in arterial structure and endothelial function in a large cohort study.109Endothelin is a potent vasoconstrictor and mitogen produced by endothelial cells under pathological conditions that contributes to abnormal control of vascular tone and blood pressure.50,110 Reriani and colleagues111 examined the effects of atrasentan, an endothelin receptor type A antagonist, on endothelial function in the coronary circulation of patients with cardiovascular risk factors and nonobstructive coronary artery disease. After 6 months of treatment, this intervention improved coronary blood flow responses to acetylcholine infusion, reflecting an improvement in microvascular endothelial function. In contrast, the intervention did not improve conduit artery endothelial function. This study provides further evidence that endothelin contributes to the regulation of arterial blood flow and endothelial dysfunction in the coronary circulation of patients.110,112Clinical Relevance of Endothelial DysfunctionAs mentioned, prior studies have shown that endothelial dysfunction in conduit arteries predicts cardiovascular disease events.7–11,13,14 Recent studies have also emphasized the importance of microvascular dysfunction, including blunted reactive hyperemia. For example, Anderson and colleagues113 showed that reactive hyperemia predicted cardiovascular events in a group of relatively healthy men. Interestingly, brachial artery flow-mediated dilation did not predict events in that study, raising the possibility that the predictive value of conduit vessel endothelial dysfunction may depend on the background risk factor profile of the patients studied. Further evidence that endothelial dysfunction relates to the pathogenesis of atherosclerosis was provided by Halcox and colleagues.6 They observed that blunted brachial artery flow-mediated dilation is associated with more marked progression of carotid artery atherosclerosis in a group of late-middle-aged individuals with intermediated cardiovascular risk. In addition to native vessel atherosclerosis, endothelial dysfunction might relate to improved patency of radial artery grafts compared with saphenous vein grafts studied 5 years after coronary bypass surgery.114Endothelial dysfunction is associated with a number of other vascular disease states, including preeclampsia115 and pulmonary hypertension.116,117 Venous thromboembolism shares many risk factors with atherosclerosis, and there is growing evidence that dysfunction of venous endothelium might be important in the pathogenesis of this disease.118 Interventions that target the vascular endothelium might have favorable effects in these conditions.119ConclusionsThis article reviews recent work published in Circulation on endothelial function. Experimental studies have provided new insight into how classic and emerging risk factors promote endothelial dysfunction and how the vascular endothelium regulates vascular homeostasis. Clinical studies have confirmed the relevance of many of these mechanisms for human disease. Furthermore, intervention studies that use endothelial function as a surrogate end point increase our understanding of the mechanisms of benefit of the intervention. In addition, such studies are important because they may provide insight into the utility of the interventions for the treatment and prevention of cardiovascular disease.Sources of FundingDr Vita is supported by the National Institutes of Health (NIH)–sponsored Boston University Medical Center Leadership Program in Vascular Medicine (K12 HL083781) and NIH grants HL083801, HL081587, HL083269, HL75795, and HL102299.DisclosuresDr Vita recently ended a consultative relationship with Angiologix, Inc., a company that is developing a device for the noninvasive study of endothelial function.FootnotesCorrespondence to Joseph A. Vita, MD, Professor of Medicine, Boston University School of Medicine, 88 E Newton St, C-818, Boston, MA 02118. 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