从滋养血管成熟化探讨稳定动脉粥样硬化易损斑块的作用

动脉粥样硬化(As)疾病在各种易损因素的影响下,最终导致斑块的形成、破裂。在这一过程中斑块内新生血管的数量、通透性成为关键因素,因此,对于新生血管的调节成为近几年As疾病的治疗策略。然而,仅仅通过抑制新生血管的进展具有一定局限性,怎样促进斑块内滋养血管成熟化将成为稳定As易损斑块新的治疗途径。本文综述了滋养血管成熟化相关生长因子及信号通路,以期为As易损斑块新的治疗奠定理论基础。     

动脉粥样硬化斑块滋养血管研究

研究表明,动脉粥样硬化斑块滋养血管在促进斑块的进展、不稳定斑块的形成、斑块内出血甚至破裂方面有着不可忽视的作用。随着对不同阶段斑块滋养血管新生机制研究的进一步深入,针对其进行有效的干预进而达到延缓斑块进展、增加斑块稳定性的目的也将成为可能,这或许能够为临床治疗动脉粥样硬化疾病提供新的策略和理念。     

外膜滋养血管在动脉粥样硬化易损斑块中的研究现状

随着对动脉粥样硬化(As)的深入研究,促进易损斑块的稳定性成为As新的治疗理念。在As"由内而外"学说中血管内膜的病理改变成为始动因素,然而近年研究表明外膜新生滋养血管(VV)在As"由外向内"发病机制中起到关键作用,总之,对于As的治疗已从保护血管内膜转变为调节外膜VV。     

高血压血管重构研究进展——多因素协同作用机制

目的本课题组针对至今难以解释临床上动脉粥样硬化(As)易损斑块发生在高切应力区域的现象,在前人和本室前期研究基础上,从血管新生的视角入手,提出血管新生是导致As易损斑块发生在狭窄上游高切应力区域的重要因素、切应力通过Id1-p53信号通路调控血管新生的理论假设,并通过实验予以验证。方法通过动物模型和体外实验相结合研究切应力如何调控斑块内血管新生和易损斑块的形成及Id1-p53信号途径调控血管新生的机制。结果通过构建兔颈动脉狭窄模型发现,易损斑块主要发生在狭窄血管近心端的高切应力区域,高切应力区域斑块内有大量的血管新生,并且大部分的新生血管为周细胞、外膜不完整的容易破裂的微血管。体外实验的研究发现转录因子Id1蛋白的表达和分布受切应力和氧化型低密度脂蛋白的调控。并且Id1-p53信号通路是切应力和氧化型低密度脂蛋白调控血管新生的重要信号通路。目前正进一步通过使用血管新生抑制剂TNP-470在体验证血管新生就是高切应力引起易损斑块形成的重要因素。结论斑块形成引起的狭窄血管近心端的高切应力主要是通过促进斑块内血管新生引起易损斑块的形成,Id1-p53信号通路是切应力调控血管新生的重要信号通路。本研究不仅有助于阐明易...     

新生滋养血管在动脉粥样硬化斑块进展中的作用

滋养血管新生作为动脉粥样硬化斑块发生发展中的关键环节已受到普遍关注,在动脉内膜发生缺血缺氧或炎症时可诱发滋养血管新生,并通过白细胞征募和斑块内出血等机制影响斑块的稳定性.     

内皮祖细胞与粥样斑块稳定性研究进展

动脉粥样硬化是最常见的和最具危害性的疾病,给人民健康带来很大威胁,而粥样斑块内滋养血管新生,加重斑块负担,使斑块由稳定状态转变为不稳定状态,增加患者发生急性心肌梗死、脑卒中等的风险。由骨髓衍生的内皮祖细胞,促进再内皮化恢复血管受损内皮的完整性,同时增加缺血缺氧部位的血管新生,对粥样斑块形成及发展均产生影响。因此现将重点探讨内皮祖细胞与滋养血管的关系及对动脉粥样硬化斑块稳定性的影响。     

颈动脉粥样硬化斑块内新生血管的研究现状及进展

颈动脉粥样硬化斑块破裂是导致脑卒中的重要原因之一,大量研究证实颈动脉斑块内新生血管是导致斑块内出血、斑块破裂的重要因素。炎症因子及各类细胞通过斑块内新生血管进入斑块,导致斑块稳定性破坏,但影响斑块内新生血管形成的重要相关因子和主要机制目前尚未完全明确,因此识别斑块内新生血管、探索斑块内新生血管形成的相关因子及机制是研究斑块内新生血管致斑块不稳定性的关键。抑制斑块内新生血管生成,可能成为防治颈动脉斑块破裂、降低脑栓塞事件发生的新策略。本综述旨在探讨颈动脉斑块内新生血管形成的相关因子、机制以及检测成像的最新研究进展,为动脉粥样硬化的诊疗提供支持。     

动脉粥样硬化病变处血管新生的病理意义

发生动脉粥样硬化的冠状动脉内膜往往出现血管新生.这些新生血管可以促进粥样硬化病变的发展,甚至诱发斑块出血和斑块破裂.进一步研究新生血管的发生机制及其病理生理意义并寻求较佳的防治方法,可以为认识动脉粥样硬化的发病机制和防治动脉粥样硬化提供一个新的视点.     

颅内动脉瘤滋养血管的研究进展

滋养血管是一种存在于血管壁内的特殊微血管结构,对血管壁的生理、病理改变起重要作用。滋养血管在颅内动脉瘤病理样本中普遍存在,未破裂与破裂动脉瘤的滋养血管微结构不同。心脑血管领域关于血管新生的分子生物学和免疫学研究可为颅内动脉瘤滋养血管的发生发展研究提供借鉴。该文从滋养血管对血管壁的生理作用、颅内动脉滋养血管的分布、颅内动脉瘤滋养血管的临床意义以及影响颅内动脉瘤滋养血管的可能因素4方面进行综述,以期为临床干预颅内动脉瘤滋养血管的发生提供思路。     

单个核细胞分化的命运与动脉粥样硬化

血管新生是指在原来存在的血管结构上长出新血管的生物学过程。急性冠状动脉综合征(ACS)主要为斑块破裂和血栓形成所引起,斑块内血管新生是斑块破裂的一个重要危险因素。而力学微环境与血管新生及微血管破裂关系密切,现阐述力学环境与斑块内血管新生的关系。①血管新生的力学微环境。动脉粥样硬化斑块因血管平滑肌细胞大量增殖和胶原大量沉积,引起微血管内腔压力增加,包括外膜的血管网所受压力上升,血管网血流压力梯度增强,局部....     

Atherosclerotic plaque rupture: local or systemic process?

It is generally established that the unstable plaque is the major cause of acute clinical sequelae of atherosclerosis. Unfortunately, terms indicating lesions prone to plaque instability, such as "vulnerable plaque," and the different phenotypes of unstable plaques, such as plaque rupture, plaque fissuring, intraplaque hemorrhage, and erosion, are often used interchangeably. Moreover, the different phenotypes of the unstable plaque are mostly referred to as plaque rupture. In the first part of this review, we will focus on the definition of true plaque rupture and the definitions of other phenotypes of plaque instability, especially on intraplaque hemorrhage, and discuss the phenotypes of available animal models of plaque instability. The second part of this review will address the pathogenesis of plaque rupture from a local and a systemic perspective. Plaque rupture is thought to occur because of changes in the plaque itself or systemic changes in the patient. Interestingly, contributing factors seem to overlap to a great extent and might even be interrelated. Finally, we will propose an integrative view on the pathogenesis of plaque rupture.     

Vulnerable atherosclerotic plaque: emerging challenge for animal models

A recent shift in the clinical paradigm of acute coronary syndromes led to a burst of activity in developing animal models related to plaque vulnerability. In the present review, animal models of spontaneous and induced plaque rupture, thrombosis, and hemorrhage and "vulnerability endpoints" in conventional models of atherosclerosis are discussed. These endpoints include readouts related to biomechanical properties of the plaques, collagen turnover, underlying inflammation, and lipid accumulation. Challenges in model validation are emphasized. Development of new animal models and new tools of monitoring plaque vulnerability will facilitate design of plaque-stabilizing therapies.     

Platelets enter atherosclerotic plaque via intraplaque microvascular leakage and intraplaque hemorrhage: a histopathological study in carotid plaques

BackgroundPlatelets foster an inflammatory environment that influences atherosclerotic lesion progression and facilitates plaque rupture, in addition to their role in acute thrombus formation. The route of entry of platelets into the atherosclerotic plaque and their exact location inside the plaque are however not completely understood.Methods and results188 carotid plaques were examined for the presence of platelets using immunohistochemistry (CD42b), and 76/188 (40.4%) were platelet positive. Platelets were observed in intraplaque hemorrhages, around plaque microvessels, mostly without leakage of erythrocytes; and in mural thrombi. Platelet positive staining was associated with a higher plaque microvessel density, and elevated plaque-levels of interleukin-8.ConclusionDue to their short life span, platelets reflect recent bleeding. It can be hypothesized that platelets might serve as a marker for leaky microvessels inside atherosclerotic plaques that are at risk for development, or progression of plaque hemorrhage.     

Animal models of spontaneous plaque rupture: The holy grail of experimental atherosclerosis research

Throughout the history of atherosclerosis research we have sought animal models of the disease process that exhibit high frequencies of the features that make human plaque a clinical risk: plaque rupture, mural thrombosis, and intra-plaque hemorrhage. This type of model is needed to determine the mechanisms by which plaques rupture and to design and test therapeutic interventions for stabilizing plaques. Studies of domestic and exotic animals have shown that most species will spontaneously develop fatty streaks and in some cases atheromatous lesions with sufficient time, but that rupture and thrombosis is exceedingly rare. Even with addition of fat and cholesterol to the diet, lesion development is accelerated but does not increase the frequency with which plaques rupture in most animal models. However, recently we have observed high frequencies of intra-plaque hemorrhage in the innominate/brachiocephalic arteries of older, chow-fed, hyperlipidemic, apolipoprotein E-deficient mice, and high frequencies of plaque rupture with mural thrombus in younger apolipoprotein E-deficient mice fed a high-fat diet. This suggests that plaque rupture and secondary thrombosis are frequent and reproducible occurrences at specific sites in apolipoprotein E-deficient mice, and that the timing and pathobiology of the ruptures are influenced by lipid status in this murine model.     

动脉粥样硬化易损斑块的生物学标志物

多种生化分子参与了动脉粥样硬化的发生发展、斑块失稳定性和破裂过程.因此,寻找能识别易损斑块和预测斑块破裂风险的血清生物学标志物,对临床工作具有重要的指导意义.文章综述了近年来有关易损斑块生物学标志物的研究进展.     

动脉粥样硬化易损斑块的生物学标志物

多种生化分子参与了动脉粥样硬化的发生发展、斑块失稳定性和破裂过程.因此,寻找能识别易损斑块和预测斑块破裂风险的血清生物学标志物,对临床工作具有重要的指导意义.文章综述了近年来有关易损斑块生物学标志物的研究进展.     

Intravascular ultrasonic study of gender differences in ruptured coronary plaque morphology and its associated clinical presentation

Coronary plaque rupture is a phenomenon underlying most acute coronary events. Although gender is an important determinant of the incidence and clinical course of coronary atherosclerosis, its relation to plaque rupture is unknown. Therefore, we assessed gender differences in native artery plaque rupture characteristics and their related clinical presentations. There were 468 intravascular ultrasound (IVUS) preintervention images of ruptured plaques retrospectively identified. There were 328 men (81.6%) with 387 plaque ruptures and 74 women (18.4%) with 81 plaque ruptures. Patient demographics, angiographic characteristics, and qualitative and quantitative IVUS analyses of ruptured plaques were assessed. On average women were older than men (67.6 +/- 11.8 vs 62.6 +/- 11.4 years, p = 0.001) and more often presented with an acute coronary syndrome (89.2% vs 72.9%, p = 0.003). Older women had smaller vessel areas at the rupture site (p = 0.001), minimum lumen site (p = 0.002), and reference segments (p = 0.002) and smaller lumen areas at the rupture site (p = 0.026) and reference segments (p = 0.03). Ruptured plaques in older women were more often associated with IVUS-evident thrombus (48.1% vs 34.6%, p = 0.022). Independent predictors of acute clinical presentation were female gender (p = 0.006), smoking (p = 0.013), and presence of thrombus (p = 0.049). Independent predictors of the presence of thrombus were female gender (p = 0.025), smaller lumen area (p = 0.023) and larger plaque area (p = 0.008) at the rupture site, longer plaque ruptures (p = 0.016), and smoking (p = 0.045). In conclusion, coronary plaque ruptures are more often associated with thrombus and acute presentations in women than in men.     

Dietary supplementation with methionine and homocysteine promotes early atherosclerosis but not plaque rupture in ApoE-deficient mice

Hyperhomocysteinemia is an independent risk factor for atherothrombosis. However, causality is unproven, and it remains unknown whether hyperhomocysteinemia promotes atherosclerosis, plaque rupture, and/or thrombosis. We evaluated the short- and long-term effects of hyperhomocysteinemia on plaque size and structure in 99 atherosclerosis-prone apolipoprotein E-deficient mice. Hyperhomocysteinemia was induced by methionine (Met) or homocysteine (HcyH) supplementation: low Met (+11 g Met/kg food), high Met (+33 g Met/kg food), low HcyH (0.9 g HcyH/L drinking water), and high HcyH (1.8 g HcyH/L drinking water). Met and HcyH supplementation significantly raised plasma total homocysteine levels by 4- to 16-fold above those observed in mice fed a control diet (up to 146.1 micromol/L). Compared with controls, aortic root plaque size was significantly larger in supplemented groups after 3 months (56% and 173% larger in high-Met and high-HcyH, respectively) but not after 12 months. Hyperhomocysteinemia was associated with an increase in the amount of collagen in plaques after both 3 and 12 months. Mechanical testing of the tail tendons revealed no weakening of collagen after 12 months of hyperhomocysteinemia. Many plaques in both control and supplemented mice appeared rupture prone morphologically, but all aortic root plaques and all but 1 coronary plaque had an intact surface without rupture or thrombosis. Thus, diet-induced hyperhomocysteinemia promotes early atherosclerosis and plaque fibrosis but does not, even in the long term, weaken collagen or induce plaque rupture.     

Melatonin stabilizes rupture‐prone vulnerable plaques via regulating macrophage polarization in a nuclear circadian receptor RORα‐dependent manner

Rupture of vulnerable plaques is the main trigger of acute cardio‐cerebral vascular events, but mechanisms responsible for transforming a stable atherosclerotic into a vulnerable plaque remain largely unknown. Melatonin, an indoleamine hormone secreted by the pineal gland, plays pleiotropic roles in the cardiovascular system; however, the effect of melatonin on vulnerable plaque rupture and its underlying mechanisms remains unknown. Here, we generated a rupture‐prone vulnerable carotid plaque model induced by endogenous renovascular hypertension combined with low shear stress in hypercholesterolemic ApoE^?/? mice. Melatonin (10 mg/kg/d by oral administration for 9 weeks) significantly prevented vulnerable plaque rupture, with lower incidence of intraplaque hemorrhage (42.9% vs. 9.5%, P = 0.014) and of spontaneous plaque rupture with intraluminal thrombus formation (38.1% vs. 9.5%, P = 0.029). Mechanistic studies indicated that melatonin ameliorated intraplaque inflammation by suppressing the differentiation of intraplaque macrophages toward the proinflammatory M1 phenotype, and circadian nuclear receptor retinoid acid receptor‐related orphan receptor‐α (RORα) mediated melatonin‐exerted vasoprotection against vulnerable plaque instability and intraplaque macrophage polarization. Further analysis in human monocyte‐derived macrophages confirmed the role of melatonin in regulating macrophage polarization by regulating the AMPKα‐STATs pathway in a RORα‐dependent manner. In summary, our data provided the first evidence that melatonin‐RORα axis acts as a novel endogenous protective signaling pathway in the vasculature, regulates intraplaque inflammation, and stabilizes rupture‐prone vulnerable plaques.