冠心病患者颈动脉粥样硬化与血管内皮功能的临床研究价值

目的:探讨颈动脉粥样硬化与血管内皮功能与冠心病患者的相关性。方法:选取114例冠心病患者(54例单支病变和60例多支病变)为观察组和60例健康体检者为对照组,对两组患者动脉粥样硬化及血管内皮功能进行分析。结果:观察组患者TC、TG、HDL及血糖水平均高于对照组,观察组LDL水平显著低于对照组,两组比较差异有统计学意义(P<0.05);观察组患者颈动脉IMT、斑块积分及斑块数明显高于对照组(P<0.05),观察组FMD显著降低(P<0.05),多支病变组病变程度更严重(P<0.05)。结论:颈动脉粥样硬化与血管内皮功能可作为预测冠心病的重要指标,对预防和治疗冠心病具有重要意义。     

Cyclic strain-mediated matrix metalloproteinase regulation within the vascular endothelium: a force to be reckoned with

The vascular endothelium is a dynamic cellular interface between the vessel wall and the bloodstream, where it regulates the physiological effects of humoral and biomechanical stimuli on vessel tone and remodeling. With respect to the latter hemodynamic stimulus, the endothelium is chronically exposed to mechanical forces in the form of cyclic circumferential strain, resulting from the pulsatile nature of blood flow, and shear stress. Both forces can profoundly modulate endothelial cell (EC) metabolism and function and, under normal physiological conditions, impart an atheroprotective effect that disfavors pathological remodeling of the vessel wall. Moreover, disruption of normal hemodynamic loading can be either causative of or contributory to vascular diseases such as atherosclerosis. EC-matrix interactions are a critical determinant of how the vascular endothelium responds to these forces and unquestionably utilizes matrix metalloproteinases (MMPs), enzymes capable of degrading basement membrane and interstitial matrix molecules, to facilitate force-mediated changes in vascular cell fate. In view of the growing importance of blood flow patterns and mechanotransduction to vascular health and pathophysiology, and considering the potential value of MMPs as therapeutic targets, a timely review of our collective understanding of MMP mechanoregulation and its impact on the vascular endothelium is warranted. More specifically, this review primarily summarizes our current knowledge of how cyclic strain regulates MMP expression and activation within the vascular endothelium and subsequently endeavors to address the direct and indirect consequences of this on vascular EC fate. Possible relevance of these phenomena to vascular endothelial dysfunction and pathological remodeling are also addressed.     

Fatty acids and signalling in endothelial cells

The endothelium is critical for the maintenance of a proper vessel function. Disturbances of endothelial function, called endothelial dysfunction, have serious implications, and lead to the development of atherosclerosis. It is well established that the risk for atherosclerosis development is influenced by nutritional factors such as the intake of certain fatty acids. Due to the fundamental role of the endothelium for atherosclerosis development, it is, therefore, likely that fatty acids directly influence the function of endothelial cells. The present review aims to explain the divergent effects of different types of fatty acids on cardiovascular disease risk by summarizing in vitro-data on the effects of fatty acids on (1) important signalling pathways involved in the modulation of endothelial cell function, and (2) endothelial cell functional properties, namely vasoactive mediator release and mononuclear cell recruitment, both of which are typically dysregulated during endothelial dysfunction.     

Transcutaneous vascular ultrasound in hypercholesterolaemic rabbits: a new method to evaluate endothelial function

Measurement of endothelial function in patients with atherosclerosis and lipid disorders is an important tool for the risk evaluation of a cardiovascular event, such as acute myocardial infarction and stroke. The feasibility of measuring endothelial function non-invasively in animal models has been limited so far. Therefore, we compared the assessment of endothelial function by in vivo transcutaneous vascular ultrasound (TVU) with the classical method of ex vivo organ bath, using the carotid artery of hypercholesterolaemic and normocholesterolaemic rabbits. The assessments of endothelial function by both techniques were performed on the same segments of the carotid artery. Vascular ultrasound detected impaired endothelium-dependent vasorelaxation induced by acetylcholine in the common carotid artery of hypercholesterolaemic rabbits. These results strongly correlated with measurements of endothelial function of isolated carotid artery rings. Furthermore, atherogenic diet caused significant fatty streak formation in the aorta, as well as significant increase of C-reactive protein and cholesterol levels. Endothelial function, an early marker of cardiovascular risk, could be non-invasively assessed and graded by TVU measurements. It correlated highly with vasoreactivity of isolated vessels in an organ bath (r(2)=0.68). We conclude that vascular ultrasound in hypercholesterolaemic rabbits is a valid method for evaluating endothelial function associated with atherosclerosis.     

NHLBI workshop report: endothelial cell phenotypes in heart, lung, and blood diseases

Endothelium critically regulates systemic andpulmonary vascular function, playing a central role in hemostasis,inflammation, vasoregulation, angiogenesis, and vascular growth.Indeed, the endothelium integrates signals originating in thecirculation with those in the vessel wall to coordinate vascularfunction. This highly metabolic role differs significantly from thehistoric view of endothelium, in which it was considered to be merelyan inert barrier. New lines of evidence may further change ourunderstanding of endothelium, in regard to both its origin andfunction. Embryological studies suggest that the endothelium arisesfrom different sites, including angiogenesis of endothelium frommacrovascular segments and vasculogenesis of endothelium frommicrocirculatory segments. These findings suggest an inherentphenotypic distinction between endothelial populations based on theirdevelopmental origin. Similarly, diverse environmental cues influenceendothelial cell phenotype, critical to not only normal function butalso the function of a diseased vessel. Consequently, an improvedunderstanding of site-specific endothelial cell function is essential,particularly with consideration to environmental stimuli present bothin the healthy vessel and in development of vasculopathic diseasestates. The need to examine endothelial cell phenotypes in the context of vascular function served as the basis for a recent workshop sponsored by the National Heart, Lung, and Blood Institute (NHLBI). This report is a synopsis of pertinent topics that were discussed, andfuture goals and research opportunities identified by the participantsof the workshop are presented.

     

Which endothelium-derived factors are really important in humans?

The endothelium plays a primary role in the local control of vascular function and structure, mainly by the production and release of NO, a potent vasodilator that also inhibits all the mechanisms involved in the pathogenesis of atherosclerosis, thus protecting the vessel wall against the development of atherosclerosis and thrombosis. Cardiovascular risk factors are associated with endothelial dysfunction, which involves enhanced production of oxygen free radicals that reduce NO availability and the release of contracting factors, including prostanoids and endothelin-1. In humans, endothelium-dependent relaxation can be assessed by tests that explore vascular reactivity. Besides the degree of vasodilation, which represents a crude estimate of endothelial function, the utilization of a complex experimental design, requiring the administration of specific agonists and antagonists, allows detailed exploration of the mediators and mechanisms involved in endothelium-dependent vasodilation. At present, the degree of endothelium-dependent vasodilation (evoked by receptor-operated agonists or the application of mechanical forces) is considered an independent predictor of cardiovascular events. In contrast, scant information is available concerning the clinical relevance of different mediators involved in endothelial function. Further studies are needed in the future to assess the specific impact of different endothelial responses on the clinical outcome in patients with cardiovascular risk factors and disease.     

Is extravasation a Fas-regulated process?

The monolayer of endothelial cells that coats the luminal surface of the vessel wall has numerous physiological functions, including the prevention of coagulation, control of vascular permeability, maintenance of vascular tone and regulation of leukocyte extravasation. Recently, we detected functional Fas ligand (FasL) expression on the endothelial lining of blood vessels. FasL induces apoptotic cell death in the multitude of cell types that express its receptor, Fas. Here, we review the function of vascular endothelium in controlling leukocyte extravasation, and illustrate how the regulation of endothelial FasL expression might contribute to this process. We also describe the role of leukocyte extravasation in angiogenesis and atherosclerosis, and we suggest that FasL gene transfer might provide a means of treating diseases of the proliferative vessel wall, particularly those that result from the detrimental infiltration of inflammatory cells.     

Atherosclerosis and calcium signalling in endothelial cells

The link between atherosclerosis and regions of disturbed flow and low wall shear stress is now firmly established, but the causal mechanisms underlying the link are not yet understood. It is now recognised that the endothelium is not simply a passive barrier between the blood and the vessel wall, but plays an active role in maintaining vascular homeostasis and participates in the onset of atherosclerosis. Calcium signalling is one of the principal intracellular signalling mechanisms by which endothelial cells (EC) respond to external stimuli, such as fluid shear stress and ligand binding. Previous studies have separately modelled mass transport of chemical species in the bloodstream and calcium dynamics in EC via the inositol trisphosphate (IP(3)) signalling pathway. We review existing models of these two phenomena, before going on to integrate the two components to provide an inclusive new model for the calcium response of the endothelium in an arbitrary vessel geometry. This enables the combined effects of fluid flow and biochemical stimulation on EC to be investigated and is the first time spatially varying, physiological fluid flow-related environmental factors have been combined with intracellular signalling in a mathematical model. Model results show that low endothelial calcium levels in the area of disturbed flow at an arterial widening may be one contributing factor to the onset of vascular disease.     

Hemodynamic regulation of metallopeptidases within the vasculature

Hemodynamic forces associated with blood flow play a vital role in the endothelial regulation of vascular tone, remodeling and the initiation and progression of vascular diseases such as atherosclerosis and hypertension. Crucial elements in endothelium-mediated events within the blood vessel are bioactive peptide signals and their associated hydrolytic enzymes. This review examines the relationship between hemodynamic forces such as shear stress and cyclic strain, and an important group of peptide-degrading enzymes within the endothelium, the thermolysin-like zinc metallopeptidases.     

Endothelial dysfunction — A major mediator of diabetic vascular disease

The vascular endothelium is a multifunctional organ and is critically involved in modulating vascular tone and structure. Endothelial cells produce a wide range of factors that also regulate cellular adhesion, thromboresistance, smooth muscle cell proliferation, and vessel wall inflammation. Thus, endothelial function is important for the homeostasis of the body and its dysfunction is associated with several pathophysiological conditions, including atherosclerosis, hypertension and diabetes. Patients with diabetes invariably show an impairment of endothelium-dependent vasodilation. Therefore, understanding and treating endothelial dysfunction is a major focus in the prevention of vascular complications associated with all forms of diabetes mellitus. The mechanisms of endothelial dysfunction in diabetes may point to new management strategies for the prevention of cardiovascular disease in diabetes. This review will focus on the mechanisms and therapeutics that specifically target endothelial dysfunction in the context of a diabetic setting. Mechanisms including altered glucose metabolism, impaired insulin signaling, low-grade inflammatory state, and increased reactive oxygen species generation will be discussed. The importance of developing new pharmacological approaches that upregulate endothelium-derived nitric oxide synthesis and target key vascular ROS-producing enzymes will be highlighted and new strategies that might prove clinically relevant in preventing the development and/or retarding the progression of diabetes associated vascular complications.     

Plasticity of endothelial cells during arterial-venous differentiation in the avian embryo

Remodeling of the primary vascular system of the embryo into arteries and veins has long been thought to depend largely on the influence of hemodynamic forces. This view was recently challenged by the discovery of several molecules specifically expressed by arterial or venous endothelial cells. We here analysed the expression of neuropilin-1 and TIE2, two transmembrane receptors known to play a role in vascular development. In birds, neuropilin-1 was expressed by arterial endothelium and wall cells, but absent from veins. TIE2 was strongly expressed in embryonic veins, but only weakly transcribed in most arteries. To examine whether endothelial cells are committed to an arterial or venous fate once they express these specific receptors, we constructed quail-chick chimeras. The dorsal aorta, carotid artery and the cardinal and jugular veins were isolated together with the vessel wall from quail embryos between embryonic day 2 to 15 and grafted into the coelom of chick hosts. Until embryonic day 7, all grafts yielded endothelial cells that colonized both host arteries and veins. After embryonic day 7, endothelial plasticity was progressively lost and from embryonic day 11 grafts of arteries yielded endothelial cells that colonized only chick arteries and rarely reached the host veins, while grafts of jugular veins colonized mainly host veins. When isolated from the vessel wall, quail aortic endothelial cells from embryonic day 11 embryos were able to colonize both host arteries and veins. Our results show that despite the expression of arterial or venous markers the endothelium remains plastic with regard to arterial-venous differentiation until late in embryonic development and point to a role for the vessel wall in endothelial plasticity and vessel identity.     

Roles of fluid shear stress in physiological regulation of vascular structure and function

The effects of fluid shear stress on the function and structure of the vascular system are outlined, based on the findings obtained in our laboratory or of our colleagues. First, it is pointed out that the adaptive response of the vascular wall to flow changes which we observed in the canine carotid artery shunted with the jugular vein altering the internal diameter to keep the wall shear stress constant, can attain the optimum vascular branching structure as predicted in the minimum work model by Murray. Electronmicroscopic studies of similarly shunted arteries revealing various morphological changes in the endothelial cells have suggested that the shear stress initially affects the endothelium. The in vitro experiments using cultured endothelial cells as well have exhibited that the mitotic activity of the cells significantly increases by applying fluid shear stress. From these findings, it is concluded that the adaptive response of the endothelium to the fluid shear stress is an inherent and key process locally regulating the vascular system to be in the most functional state.     

Chronic excessive erythrocytosis induces endothelial activation and damage in mouse brain

Excessive erythrocytosis results in severely increased blood viscosity, which may have significant detrimental effects on endothelial cells and, ultimately, function of the vascular endothelium. Because blood-brain barrier stability is crucial for normal physiological function, we used our previously characterized erythropoietin-overexpressing transgenic (tg6) mouse line (which has a hematocrit of 0.8-0.9) to investigate the effect of excessive erythrocytosis on vessel number, structure, and integrity in vivo. These mice have abnormally high levels of nitric oxide (NO), a potent proinflammatory molecule, suggesting altered vascular permeability and function. In this study, we observed that brain vessel density of tg6 mice was significantly reduced (16%) and vessel diameter was significantly increased (15%) compared with wild-type mice. Although no significant increases in vascular permeability under normoxic or acute hypoxic conditions (8% O2 for 4 h) were detected, electron-microscopic analysis revealed altered morphological characteristics of the tg6 endothelium. Tg6 brain vascular endothelial cells appeared to be activated, with increased luminal protrusions reminiscent of ongoing inflammatory processes. Consistent with this observation, we detected increased levels of intercellular adhesion molecule-1 and von Willebrand factor, markers of endothelial activation and damage, in brain tissue. We propose that chronic excessive erythrocytosis and sustained high hematocrit cause endothelial damage, which may, ultimately, increase susceptibility to vascular disease.     

Defensins and cathelicidins: neutrophil peptides with roles in inflammation, hyperlipidemia and atherosclerosis

Atherosclerosis is a disease that begins in fetal life and represents a leading cause of morbidity and mortality associated with significant socioeconomic consequences. A central concept with regard to its pathogenesis is that of endothelial cell dysfunction, which is associated with the release of a large number of mediators secreted by leukocytes that are present in large numbers at the sites of atheroma formation. Neutrophil peptides defensins and cathelicidins are essential elements of the innate immunity and have been present in high concentrations in atherosclerotic plaques in humans. Recently, their role as potential mediators of vascular disease was investigated. Defensins are involved in the lipoprotein metabolism in the vessel wall, favoring LDL and lipoprotein (a) accumulation and modification in the endothelium and the extracellular matrix. They also interfere with the vascular smooth muscle cell function, exhibit prothrombotic activity, and play an inhibitory role in various phases of angiogenesis. Cathelicidins were recently found to enhance endothelial proliferation in cultures, induce functionally significant angiogenesis in animal models, and regulate endothelial cell apoptosis. Further study of these peptides could provide useful insight in the relationship between inflammation and atherosclerosis and is anticipated to have therapeutic and prognostic ramifications.     

Purinergic receptors mediate endothelial dysfunction and participate in atherosclerosis

Atherosclerosis is the main pathological basis of cardiovascular disease and involves damage to vascular endothelial cells (ECs) that results in endothelial dysfunction (ED). The vascular endothelium is the key to maintaining blood vessel health and homeostasis. ED is a complex pathological process involving inflammation, shear stress, vascular tone, adhesion of leukocytes to ECs, and platelet aggregation. The activation of P2X4, P2X7, and P2Y2 receptors regulates vascular tone in response to shear stress, while activation of the A2A, P2X4, P2X7, P2Y1, P2Y2, P2Y6, and P2Y12 receptors promotes the secretion of inflammatory cytokines. Finally, P2X1, P2Y1, and P2Y12 receptor activation regulates platelet activity. These purinergic receptors mediate ED and participate in atherosclerosis. In short, P2X4, P2X7, P2Y1, and P2Y12 receptors are potential therapeutic targets for atherosclerosis.     

Classical cardiovascular disease risk factors associate with vascular function and morphology in rheumatoid arthritis: a six-year prospective study

Introduction

Patients with rheumatoid arthritis (RA) are at an increased risk for cardiovascular disease (CVD). An early manifestation of CVD is endothelial dysfunction which can lead to functional and morphological vascular abnormalities. Classical CVD risk factors and inflammation are both implicated in causing endothelial dysfunction in RA. The objective of the present study was to examine the effect of baseline inflammation, cumulative inflammation, and classical CVD risk factors on the vasculature following a six-year follow-up period.

Methods

A total of 201 RA patients (155 females, median age (25th to 75th percentile): 61 years (53 to 67)) were examined at baseline (2006) for presence of classical CVD risk factors and determination of inflammation using C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). At follow-up (2012) patients underwent assessments of microvascular and macrovascular endothelium-dependent and endothelium-independent function, along with assessment of carotid atherosclerosis. The CRP and ESR were recorded from the baseline study visit to the follow-up visit for each patient to calculate cumulative inflammatory burden.

Results

Classical CVD risk factors, but not RA disease-related inflammation, predicted microvascular endothelium-dependent and endothelium-independent function, macrovascular endothelium-independent function and carotid atherosclerosis. These findings were similar in a sub-group of patients free from CVD, and not receiving non-steroidal anti-inflammatory drugs, cyclooxygenase 2 inhibitors or biologics. Cumulative inflammation was not associated with microvascular and macrovascular endothelial function, but a weak association was apparent between area under the curve for CRP and carotid atherosclerosis.

Conclusions

Classical CVD risk factors may be better long-term predictors of vascular function and morphology than systemic disease-related inflammation in patients with RA. Further studies are needed to confirm if assessments of vascular function and morphology are predictive of long-term CV outcomes in RA.     

C-型钠尿肽与血管损伤性疾病

C-型钠尿肽(C-type natriuretic peptide, CNP)作为钠尿肽家系的一员, 主要是由血管内皮分泌,CNP与血管平滑肌细胞钠尿肽受体-B(NPR-B)结合,激活颗粒型鸟苷酸环化酶,促进细胞内cGMP 水平升高,以旁分泌和/或自分泌方式调节循环系统功能稳态.CNP广泛分布于血管系统,尤其在内皮细胞中高表达.CNP具有利钠、利尿、调节血管张力、抑制血管平滑肌细胞迁移、增殖等作用,与高血压、动脉粥样硬化、血栓形成、冠脉成形术后再狭窄和血管钙化等多种血管损伤性疾病密切相关.     

Approaches for non-invasive assessment of endothelial function: focus on peripheral arterial tonometry

The arterial endothelium is a complex organ that modulates vascular tone by release of various substances to control perfusion. Endothelial function reflects vascular ageing and health. Already at the earliest stages of atherosclerosis the delicate balance between arterial constriction and relaxation is disturbed. Therefore, non-invasive assessment of endothelial function is a means to identify patients at increased cardiovascular risk, even at levels of disease that cannot be identified with classical imaging techniques that depict arterial wall and/or lumen or with functional assessment of ischaemia. Currently, there is an increasing interest in the early recognition of endothelial dysfunction to streamline and optimise preventive therapeutic measures. In this article, several methods for the assessment of endothelial function are briefly reviewed. In particular, we discuss the fast bed-side assessment of endothelial function by the reactive hyperaemia peripheral arterial tonometry (RH-PAT) method.     

Lipid peroxidation and endothelial cell injury: implications in atherosclerosis

Vascular endothelial cells, which play an active role in the physiological processes of vessel tone regulation and vascular permeability, form a border separating deeper layers of the blood vessel wall and cellular interstitial space from the blood and circulating cells. Damage or dysfunction of endothelial cells may reduce the effectiveness of the endothelium to act as a selectively permeable barrier to plasma components, including cholesterol-rich lipoprotein remnants. This may be involved in the etiology of atherosclerosis. Experimental evidence indicates that free radical-mediated lipid peroxidation can induce endothelial cell injury/dysfunction. Reactive oxygen species, including peroxidized lipids capable of initiating cell injury, may be generated within endothelial cells, be present in plasma components, or be derived from neutrophils or other blood-borne cells. Lipid peroxidation could initiate or promote the process of atherosclerotic lesion formation by directly damaging endothelial cells, and by enhancing the adhesion and activation of neutrophils and the susceptibility of platelets to aggregate. Endothelial cell injury by lipid hydroperoxides also could increase the uptake of LDL into the vessel wall. These events and other cellular dysfunctions may individually or collectively initiate and/or help to sustain the development of atherosclerosis.     

Inflammation,oxidative stress and renin angiotensin system in atherosclerosis

Atherosclerosis is a chronic inflammatory disease associated with cardiovascular dysfunction including myocardial infarction, unstable angina, sudden cardiac death, stroke and peripheral thromboses. It has been predicted that atherosclerosis will be the primary cause of death in the world by 2020. Atherogenesis is initiated by endothelial injury due to oxidative stress associated with cardiovascular risk factors including diabetes mellitus, hypertension, cigarette smoking, dyslipidemia, obesity, and metabolic syndrome. The impairment of the endothelium associated with cardiovascular risk factors creates an imbalance between vasodilating and vasoconstricting factors, in particular, an increase in angiotensin Ⅱ(Ang Ⅱ) and a decrease in nitric oxide. The renin-angiotensin system(RAS), and its primary mediator Ang Ⅱ, also have a direct influence on the progression of the atherosclerotic process via effects on endothelial function, inflammation, fibrinolytic balance, and plaque stability. Anti-inflammatory agents [statins, secretory phospholipase A2 inhibitor, lipoprotein-associated phospholipase A2 inhibitor, 5-lipoxygenase activating protein, chemokine motif ligand-2, C-C chemokine motif receptor 2 pathway inhibitors, methotrexate, IL-1 pathway inhibitor and RAS inhibitors(angiotensin-converting enzyme inhibitors)], Ang Ⅱ receptor blockers and ranin inhibitors may slow inflammatory processes and disease progression. Several studies in human using anti-inflammatory agents and RAS inhibitors revealed vascular benefits and reduced progression of coronary atherosclerosis in patients with stable angina pectoris; decreased vascular inflammatory markers, improved common carotid intima-media thickness and plaque volume in patients with diagnosed atherosclerosis. Recent preclinical studies have demonstrated therapeutic efficacy of vitamin D analogs paricalcitol in Apo E-deficient atherosclerotic mice.