斑块内血管生成与动脉粥样硬化

血管生成在动脉粥样硬化的发生发展已日渐受到重视，它可能成为动脉粥样硬化的形成与发展的核心事件，使动脉粥样硬化的病因学发生革命性改变。     

斑块内血管生成在兔动脉粥样硬化斑块发生发展中的作用

目的观察斑块内血管生成对兔动脉粥样硬化斑块形成与发展的影响。方法用高胆固醇饲料复制动脉粥样硬化兔模型。15只日本大耳白兔随机分为3组:A组,阴性对照组,仅给普通饲料喂养,B、C组给高胆固醇饲料喂养3周,A组及B组肌注白蛋白(2μg/kg)(0d),C组肌注血管内皮生长因子(VEGF1652μg/kg),继续以前饲养方式3周处死动物,截取胸主动脉进行计量组织学及免疫组织化学分析,测定不同组别不同时间点兔血清白细胞介素8(IL8)浓度和血脂浓度。结果(1)斑块面积(A组0,B组1.81%±0.61%,C组24.12%±3.58%)、斑块周径(A组0,B组6.05%±1.62%,C组25.71%±1.97%)及斑块的最大厚度(A组0,B组0.06mm±0.002,C组0.16mm±0.007mm),各组间比较有显著差异(P<0.05)。(2)新生血管的密度(CD34阳性细胞数细胞数/mm2(cells/mm2)A组0,B组12.35±2.02,C组61.15±7.55)各组之间比较有显著差异(P<0.05)。(3)电镜显示:新生血管与动脉粥样斑块相邻,新生血管腔内可见淋巴细胞。(4)血清IL8浓度(+21d时A组[0.05±0.006]pg/ml,B组[0.808±0.308]pg/ml,C组[15.72±4.31]pg/ml)各组间相比有显著差异。(5)此时血清胆固醇浓度B,C两组相比无显著差异。结论斑块内血管生成是动脉粥样斑块的重要病理特征,这个过程可能与炎性反应有关。     

兔斑块内血管生成与动脉粥样硬化形成和发展关系的探讨

目的:观察兔斑块内血管内皮生长因子(VEGF)与动脉粥样硬化(AS)斑块形成和发展的关系。方法:15只日本大耳白兔随机分为3组:对照组用普通饲料喂养,高脂组及VFGF组给高胆固醇饲料喂养3周(21 d)后,对照组及高脂组肌内注射清蛋白2μg/kg,VEGF组肌内注射VEGF165 2μg/kg,继续以前方式饲养3周(共42 d)处死动物,截取胸主动脉进行计量组织学及免疫组织化学分析,测定不同组别不同时间点兔血清白细胞介素-8(IL-8)浓度和血脂浓度。结果:①斑块面积(PA)[对照组0,高脂组(1.81±0.61)%,VEGF组(24.12±3.58)%]、斑块周径[对照组0,高脂组(6.05±1.62)%,VEGF组(25.71±2.97)%]及斑块的最大厚度[对照组0,高脂组(0.06±0.002)mm,VEGF组(0.16±0.007)mm],各组间比较差异有统计学意义(P<0.05);②42 d 时,新生血管的密度对照组、高脂组、VEGF组之间比较差异有统计学意义(P<0.05);③电镜显示:新生血管与AS斑块相邻,新生血管腔内可见淋巴细胞。④VEGF组CD34阳性细胞数与PA之间呈正相关(r=0.989,P< 0.01)。⑤血清IL-8浓度各组间比较差异有统计学意义,但血清TC浓度高脂组与VEGF组差异无统计学意义(P>0.05)。结论:斑块内血管生成是AS斑块的重要病理特征,该过程可能与炎性反应有关。     

血管滋养血管及血管内皮生长因子与动脉粥样硬化斑块研究进展

血管滋养血管其主要功能是运送营养物质和氧至动静脉血管壁,同时清除血管壁细胞及通过动静脉血管内皮扩散转运所产生的"废物"。尽管血管滋养血管特性的改变与动脉粥样硬化斑块进展之间的关系已得到很好的证实,但血管滋养血管的作用,特别是疾病过程中如动脉粥样硬化,以何种方式存在及消失,是该疾病的成因或仅仅起作用,目前仍未完全明了。然而,即使其增值作用较小,其新生的微血管由于内皮损害而作为单核细胞移行至早期疾病位点的通路,成为疾病进展的根源之一。鉴于血管滋养血管以上两种功能特点,现就血管滋养血管及血管内皮生长因子与动脉粥样硬化斑块形成之间的关系作相关综述。     

抗血管生成--动脉粥样硬化治疗的新策略

器官和组织的血管系统形成有3种方式,即“血管发生”(vasculogenesis)、“血管生成”(angiogenesis)和“动脉生成”(arteriogenesis).“血管发生”是在胚胎形成早期,由内皮细胞的前体成血管细胞形成血管腔结构的过程;“血管生成”则是指无发育完整中膜的新血管的形成;而“动脉生成”是指有发育完整的中膜的新动脉的出现[1,2].生理意义的血管形成在胚胎发育,创伤修复和侧支循环代偿缺血等方面发挥重要作用,而病理意义的血管形成,即血管生成异常则在动脉粥样硬化(AS)[BFQ、肿瘤生长及转移、糖尿病性视网膜病变、风湿性关节炎等疾病的发生中发挥重要作用.近年来,血管生成在AS发生、发展中的作用已日益得到阐明,抗血管生成将成为AS治疗一个引人注目的新策略.     

血管内皮生长因子与动脉粥样硬化

血管内皮生长因子(VEGF)因其潜在的治疗前景引起了国内外的广泛关注。然而,近年来研究发现VEGF可促进动脉粥样硬化的发生和发展。文章就VEGF的分子特征、受体、表达调控、功能及其与动脉粥样硬化的关系作了综述。     

动脉粥样硬化斑块内血管新生的研究进展

斑块内血管新生在动脉粥样硬化的发生发展中可能是一个核心事件并起着关键性作用 ,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。     

血管内皮生长因子165对实验性兔动脉粥样硬化斑块形成的影响

目的观察血管内皮生长因子165对动脉粥样硬化斑块形成与发展的影响。方法利用高胆固醇饲料复制动脉粥样硬化兔模型。15只兔随机分为正常对照组、高胆固醇组和血管内皮生长因子组。42天时处死动物,截取胸主动脉进行计量组织学及免疫组织化学分析。结果正常对照组、高胆固醇组和血管内皮生长因子组的斑块面积(0%比1.81%±0.61%比24.12%±3.58%)、斑块周径(0比6.05%±1.62%比25.71%±1.97%)以及斑块最大厚度(0比0.06mm±0.002mm比0.16mm±0.007mm)均存在显著差异(P<0.05)。3组CD34阳性细胞数(cellsmm2)分别为0、12.35±2.02和61.15±7.55(P<0.05)。电镜显示新生血管与动脉粥样斑块相邻,新生血管腔内可见淋巴细胞。血管内皮生长因子组CD34阳性细胞数与斑块面积之间呈正相关(r=0.989,P<0.001)。结论血管内皮生长因子165能促进兔动脉粥样硬化斑块的形成与发展。     

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。     

新生血管形成与动脉粥样硬化

治疗性血管生成通过增加心肌再灌注而提高心功能、降低心肌梗死的发生率,曾被认为是治疗冠心病的新策略。但是,其给斑块的进展和稳定性带来的一些负面的影响也是不容忽视的。近年来,随着人们对斑块与新生血管形成的关系的认识增多,又有了抑制斑块内新生血管生成而抑制斑块进展和增加斑块稳定性的治疗理念。本文将综述新生血管与动脉粥样硬化斑块稳定性的关系以及抑制新生血管形成的治疗进展。     

血浆同型半胱氨酸与缺血性脑血管病患者颈动脉粥样硬化斑块的关系

目的探讨缺血性脑血管病患者血浆同型半胱氨酸（Hcy）水平与颈动脉粥样硬化斑块的关系。方法选择327例发病时间≤7 d、首次发病的缺血性脑血管病患者,其中脑梗死264例,颈内动脉系统短暂性脑缺血发作（TIA）63例。采用颈动脉彩色多普勒超声检查颈动脉内-中膜厚度（IMT）,综合评估患者颈动脉粥样硬化程度及斑块性质。并根据超声结果将患者分为IMT正常组、IMT增厚组、斑块形成组;酶联免疫吸附法测定晨起空腹血浆Hcy浓度。分析血浆Hcy水平与颈动脉粥样硬化斑块的关系。结果①327例患者中,99例为IMT正常,40例为IMT增厚,188例为粥样斑块形成。在188例斑块形成的患者中,易损斑块组82例,非易损斑块组106例。②IMT正常组、IMT增厚组、斑块形成组的血浆Hcy浓度（中位数）分别为13.6、22.3、28.6μmol/L,高同型半胱氨酸血症（HHcy）的发生率分别为40.4%（40/99）、70.0%（28/40）、75.5%（142/188）。除IMT增厚组与斑块形成组间HHcy发生率差异无统计学意义外,3组间观察指标比较差异均有统计学意义（均P〈0.05）。③易损斑块组血浆Hcy浓度和HHcy发生率分别为28.9μmol/L和82.9%,高于非易损斑块组的23.4μmol/L和69.8%,差异均有统计学意义,P〈0.05。④多因素Logistic回归分析显示,Hcy浓度增高是颈动脉粥样斑块形成的独立危险因素（OR=1.14,95%CI：1.04～1.25）结论随着血浆Hcy水平的升高,颈动脉粥样硬化程度随之升高。HHcy是颈动脉粥样硬化斑块形成的独立危险因素。     

兔动脉粥样硬化易损斑块早期预警指标的回归性研究

目的 通过对动脉粥样硬化易损斑块破裂前各项检测指标的回归分析,明确预测易损斑块破裂的最佳指标.方法 40只雄性新西兰纯种兔用球囊损伤腹主动脉+高脂喂养10周,于8周末分为p53基因组(20只)和LacZ基因组(20只),在腹主动脉斑块形成处分别转染携带人野生型p53基因或LacZ基因的重组腺病毒载体,2周后分别给予中国斑点蝰蛇毒(CRVV)和组胺药物触发斑块破裂.应用酶联免疫吸附法(ELISA)检测斑块破裂前血清中的高敏C反应蛋白(hs-CRP)、可溶性细胞间黏附分子-1(sICAM-1)和可溶性血管细胞间黏附分子(sVCAM-1)的变化,免疫比浊法测定血浆中纤维蛋白原的水平,联合应用体表超声心动图、血管内超声(IVUS)显像仪和声学密度定量(AD)技术检测易损斑块破裂前的各项影像学指标及声学密度强度,利用logistic回归分析判断以上各项检测指标与易损斑块破裂的关系.结果两组实验兔在药物触发后有21只兔共34处发生斑块破裂及血栓形成.p53基因组(存活19只)斑块破裂率89.5%(17/19),与LacZ基因组(存活18只)斑块破裂率22.2%(4/18)比较,差异有统计学意义(P＜0.01).药物触发前,斑块破裂组(n=21)hs-CRP水平、体表血管超声测值(腹主动脉内膜中层厚度、峰值速度)、AD值、IVUS测值明显高于斑块未破裂组(n=16),logistic回归分析显示IVUS测值斑块偏心指数(EI)、斑块面积(PA)和血清学sVCAM-1的OR值分别为26.917、19.301和1.339(均P＜0.05),校正的AD值AⅡ-c%的OR值为0.458(P＜0.05).结论 IVUS测值E1、PA、血清学指标sVCAM-1以及AD值是预测斑块易损性的重要指标.

Abstract：

Objective To detect the optimal predictors of vulnerable atherosclerotic plaques. Methods Forty New Zealand white rabbits underwent balloon-induced abdominal aortic wall injury and were fed a high cholesterol and saturated fat diet containing 1% cholesterol for 8 weeks. Rabbits were then randomly divided into two groups: group A ( n = 20, the aortic segments rich in plaques were incubated transluminally with recombinant adenovirus carrying p53 ) and group B [n = 20, incubated transluminally with β galactosidase (LacZ) genes]. Two weeks later, rabbits underwent pharmacological triggering with injection of Chinese Russell's viper venom (CRVV) and histamine. Before pharmacologically triggering,concentrations of hs-CRP, sVCAM-1 and sICAM-1 were measured by means of Enzyme-linkedimmunosorbent assay (ELISA). Fibrinogen was analyzed by nephelometer. Ultrasound imaging, accuracy densitometry (AD) examination and intravascular ultrasound (IVUS) were performed to analyze the in vivo features of vulnerable plaques. Logistic regression was used to detect the predictors for vulnerable plaques. Results The ratio d plaque rupture after pharmacological triggering was significantly higher in group A (89.5% ,17/19) than in group B (22.2%,4/18). Serum hs-CRP level was significantly higher in plaque rupture group than in non-rupture group before pharmacological triggering (P ＜ 0. 05 ). In the meantime, parameters derived from ultrasound imaging [intima-media thickness (IMT) and peak velocity (VP), values of accuracy densitometry], measurements of IVUS [external elastic membrance area (EEMA),plaque area(PA), plaque burden (PB), eccentric index (EI) and remodeling index(RI)]were significantly larger in plaque rupture group than in non-rupture group. Logistic regression showed that EI(OR=26.917),PA(OR=19.301), sVCAM-1(OR=1.339)and AⅡ-c%(OR=0.458)were independent predictors for plaque rupture(all P＜0.05).Conclusion The major predictors of vulnerable plaques were eccentric index (EI) and plaque area(PA), sVCAM-1 and AⅡ-c% in this model.     

Toll样受体4在胰腺癌组织中的表达及其与肿瘤血管生成的关系

目的 探讨Toll样受体4(TLR4)在胰腺癌组织中的表达及其与肿瘤血管生成的关系.方法 采用免疫组化SP法检测62例经病理证实的胰腺癌手术切除标本及35例癌旁正常胰腺组织中TLR4蛋白表达,采用CD31抗体标记微血管内皮细胞,计算微血管密度(MVD).分析TLR4蛋白表达与胰腺癌临床病理特征以及MVD的相关性.结果 胰腺癌组织TLR4蛋白阳性表达率和MVD分别为74.2％ (46/62)和47.3±13.5,均显著高于正常胰腺组织的17.1％ (6/35)和12.6±4.8(P值均＜0.01).有淋巴结转移的胰腺癌组织中TLR4蛋白阳性表达率为83.8％,显著高于无淋巴结转移的60.0％(P=0.036);TNM分期为Ⅲ+Ⅳ期的胰腺癌组织中TLR4蛋白阳性表达率为85.3％,显著高于Ⅰ+Ⅱ期的60.7％(P =0.028).MVD与肿瘤的大小、淋巴结转移及TNM分期密切相关(P值分别为0.008、0.036、0.010).胰腺癌TLR4蛋白表达与MVD呈显著正相关(Υ=0.534,P＜0.01).结论 TLR4参与胰腺癌的发生、发展,其机制可能与促进肿瘤血管生成有关.     

T lymphocytes that infiltrate tumors and atherosclerotic plaques produce heparin-binding epidermal growth factor-like growth factor and basic fibroblast growth factor: a potential pathologic role.

Despite significant infiltration into tumors and atherosclerotic plaques, the role of T lymphocytes in these pathological conditions is still unclear. We have demonstrated that tumor-infiltrating lymphocytes (TILs) and plaque-infiltrating lymphocytes (PILs) produce heparin-binding epidermal growth factor-like growth factor (HB-EGF) and basic fibroblast growth factor (bFGF) in vitro under nonspecific conditions and in vivo in tumors by immunohistochemical staining. HB-EGF and bFGF derived from TILs and PILs directly stimulated tumor cells and vascular smooth muscle cells (SMCs) in vitro, respectively, while bFGF displayed angiogenic properties. Therefore, T cells may play a critical role in the SMC hyperplasia of atherosclerosis and support tumor progression by direct stimulation and angiogenesis.     

Relationship between vascular endothelium and periodontal disease in atherosclerotic lesions: Review article

Inflammation and endothelial dysfunction are linked to the pathogenesis of atherosclerotic disease. Recent studies suggest that periodontal infection and the ensuing increase in the levels of inflammatory markers may be associated with myocardial infarction, peripheral vascular disease and cerebrovascular disease. The present article aimed at reviewing contemporary data on the pathophysiology of vascular endothelium and its association with periodontitis in the scenario of cardiovascular disease.     

Cell death in human atherosclerotic plaques involves both oncosis and apoptosis

The aim of the present study was to analyze the frequency and mechanism of cell death in atherosclerotic plaques with a recent history (<6 months) of rupture. Atherosclerotic plaques were obtained from patients with symptomatic ipsilateral carotid stenosis >70% diameter reduction undergoing carotid endarterectomy. In situ tailing and nick translation of fragmented DNA, agarose gel electrophoresis of plaque DNA and electron microscopy were used to identify cell death by apoptosis (programmed cell death) and oncosis. The mean number of cells containing fragmented DNA in the plaques was 12.7±3.5% (n=15). Focal accumulations of cells with DNA fragmentation occurred in the fibrous cap, at sites of rupture, close to lipid deposits and necrosis and was always accompanied by the presence of inflammatory cells. Electrophoretic separation of DNA isolated from part of plaques, where the presence of DNA fragmentation had previously been demonstrated by in situ DNA nick translation, resulted in multiple ladders of 180–200 base pairs characteristic of apoptosis. Electron microscopic analysis revealed presence of cells with morphological signs of degeneration in a frequency even higher than that found by in situ nick translation. Some of these cells had a characteristic apoptotic appearance with condensed chromatin and cytoplasm, but the large majority of the cells had an ultrastructure typical for cells undergoing cell death by oncosis with membrane disruption and swollen, disintegrating organelles. Thus, although apoptosis clearly takes place in atherosclerotic plaques, oncosis appears to be a much more common mechanism for cell death.     

非编码RNA与消化系统疾病的关系

近年来随着对微小RNA及小干扰RNA等的深入研究,人们逐渐认识到非编码RNA是一大类重要的基因调控因子,并在许多疾病的诊断、治疗、预后中起独特的作用。本文总结了近年来非编码RNA（ncRNA）在消化系统疾病的研究进展,探讨值得关注的研究方向。