Pharmacological approaches to improve endothelial repair mechanisms

Endothelial injury is thought to play a pivotal role in the development and progression of vascular diseases, such as atherosclerosis, hypertension or restenosis, as well as their complications, including myocardial infarction or stroke. Accumulating evidence suggests that bone marrow-derived endothelial progenitor cells (EPCs) promote endothelial repair and contribute to ischemia-induced neovascularization. Coronary artery disease and its risk factors, such as diabetes, hypercholesterolemia, hypertension and smoking, are associated with a reduced number and impaired functional activity of circulating EPCs. Moreover, initial data suggest that reduced EPC levels are associated with endothelial dysfunction and an increased risk of cardiovascular events, compatible with the concept that impaired EPC-mediated vascular repair promotes progression of vascular disease. In this review we summarize recent data on the effects of pharmacological agents on mobilization and functional activity of EPCs. In particular, several experimental and clinical studies have suggested that statins, angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers, PPAR-γ agonists and erythropoietin increase the number and functional activity of EPCs. The underlying mechanisms remain largely to be defined; however, they likely include activation of the PI3-kinase/Akt pathway and endothelial nitric oxide synthase, as well as inhibition of NAD(P)H oxidase activity of progenitor cells.     

Intravenously injected human multilineage-differentiating stress-enduring cells selectively engraft into mouse aortic aneurysms and attenuate dilatation by differentiating into multiple cell types

Objectives

Aortic aneurysms result from the degradation of multiple components represented by endothelial cells, vascular smooth muscle cells, and elastic fibers. Cells that can replenish these components are desirable for cell-based therapy. Intravenously injected multilineage-differentiating stress-enduring (Muse) cells, endogenous nontumorigenic pluripotent-like stem cells, reportedly integrate into the damaged site and repair the tissue through spontaneous differentiation into tissue-compatible cells. We evaluated the therapeutic efficacy of Muse cells in a murine aortic aneurysm model.

建立以CFSE标记细胞微球为参照检测人外周血EPC数量的方法及其临床意义

建立以CFSE标记细胞微球做参照,以流式单平台检测EPC数量的方法并评价其临床应用效果。使用流式单平台计数,利用CFSE染色的荧光细胞微球作为内参照,分析标本中的EPC的数量,并与体外克隆计数相比较。基于流式单平台利用CFSE标记细胞微球参照检测人外周血EPC数量和体外克隆计数的结果一致,但是相对体外克隆方法来说,我们建立的方法实验时间和成本明显降低,技术要求也相应降低。基于流式单平台利用CFSE标记细胞微球参照检测人外周血EPC数量的方法能够更快更准确的检测EPC数量,节约时间和成本,更适合临床常规使用。     

Erythropoietin improves myocardial performance in doxorubicin-induced cardiomyopathy.

AIMS: Doxorubicin (Dox) is a potent chemotherapeutic agent associated with severe cardiotoxicity. Erythropoietin (Epo) has recently been shown to exhibit proangiogenic properties related to endothelial progenitor cell (EPC) mobilization. We tested the hypothesis that EPC are compromised in rats with Dox-induced cardiotoxicity and correction of this functional impairment by treatment with Epo could result in attenuation of myocardial dysfunction. METHODS AND RESULTS: Wistar rats were either treated with two different doses of Epo (20U or 200U) or PBS (n = 40 in each group) for four consecutive weeks, followed by Dox administration. In a second study, EPC obtained from healthy rats were transfused intravenously (n = 20/group) prior to induction of Dox cardiomyopathy. EPC from healthy subjects were evaluated for their proliferative and migratory properties in the presence or absence of Dox and Epo pre-treatment. Echocardiography demonstrated an improvement in fractional shortening (FS) in Epo-treated rats. Epo treatment was associated with a reduced mortality in both Epo-treated groups. Circulating EPC numbers were three times higher in Epo-treated compared with non-treated animals. Adhesive properties, migration, and tube formation capacity in matrigel of EPCs from both Epo-treated groups as compared with controls were significantly enhanced. EPC transfer to Dox-treated rats led to functional myocardial improvement equivalent to the protection afforded by treatment with Epo. In EPC obtained from humans, pre-incubation with Epo significantly attenuated the anti-proliferative and anti-migratory effects of treatment with Dox. CONCLUSION: Epo treatment is potentially protective against myocardial dysfunction induced by Dox. These effects are partially mediated by enhancement in the number of EPC and their functional properties.     

Exercise acutely increases circulating endothelial progenitor cells and monocyte-/macrophage-derived angiogenic cells

OBJECTIVES: We investigated whether a single episode of exercise could acutely increase the numbers of endothelial progenitor cells (EPCs) and cultured/circulating angiogenic cells (CACs) in human subjects. BACKGROUND: Endothelial progenitor cells and CACs can be isolated from peripheral blood and have been shown to participate in vascular repair and angiogenesis. We hypothesized that exercise may acutely increase either circulating EPCs or CACs. METHODS: Volunteer subjects (n = 22) underwent exhaustive dynamic exercise. Blood was drawn before and after exercise, and circulating EPC numbers as well as plasma levels of angiogenic growth factors were assessed. The CACs were obtained by culturing mononuclear cells and the secretion of multiple angiogenic growth factors by CACs was determined. RESULTS: Circulating EPCs (AC133+/VE-Cadherin+ cells) increased nearly four-fold in peripheral blood from 66 +/- 27 cells/ml to 236 +/- 34 cells/ml (p < 0.05). The number of isolated CACs increased 2.5-fold from 8,754 +/- 2,048 cells/ml of peripheral blood to 20,759 +/- 4,676 cells/ml (p < 0.005). Cultured angiogenic cells isolated before and after exercise showed similar secretion patterns of angiogenic growth factors. CONCLUSIONS: Our study demonstrates that exercise can acutely increase EPCs and CACs. Given the ability of these cell populations to promote angiogenesis and vascular regeneration, the exercise-induced cell mobilization may serve as a physiologic repair or compensation mechanism.     

设计总承包在北京电力医院改扩建项目中的应用

介绍了设计总承包的定义、特点和主要工作流程,阐述了其在北京电力医院改扩建工程中的具体应用,总结了设计总承包在工程建设中的应用效果及价值。     

Delivery of progenitor cells with injectable shear-thinning hydrogel maintains geometry and normalizes strain to stabilize cardiac function after ischemia

Objectives

The ventricle undergoes adverse remodeling after myocardial infarction, resulting in abnormal biomechanics and decreased function. We hypothesize that tissue-engineered therapy could minimize postischemic remodeling through mechanical stress reduction and retention of tensile myocardial properties due to improved endothelial progenitor cell retention and intrinsic biomechanical properties of the hyaluronic acid shear-thinning gel.

Biofunctionalization of synthetic bone substitutes with angiogenic stem cells: Influence on regeneration of critical-size bone defects in an in vivo murine model

Purpose

The aim of this study was to investigate the influence of human bone marrow?derived endothelial progenitor cells (EPC) on vascularization and bone regeneration in combination with a bone-substitute material (BSM) in a critical-size bone defect in a murine model. Critical-size bone defects were performed and the defects were filled according to the group membership.

内皮祖细胞移植对糖尿病兔下肢缺血的病理及血管内皮生长因子的影响

目的探讨内皮祖细胞(EPC)移植治疗糖尿病兔下肢缺血的病理及缺血肌肉中血管内皮生长因子(VEGF)的变化。方法2006年1月至9月在哈尔滨医科大学附属第二医院内分泌科将30只健康日本大耳白兔随机分为3组,即糖尿病磷酸盐缓冲液(PBS)对照组(A组)8只、糖尿病内皮祖细胞移植治疗组(B组)14只、正常血糖内皮祖细胞移植治疗组(C组)8只。骨髓来源的内皮祖细胞经体外扩增培养7d后,通过肌内注射进行细胞移植,用病理改变及肌浆中VEGF的变化评价治疗效果。结果EPC移植后14d,病理示3组毛细血管密度分别为(9.29±1.63)个/视野、(12.60±2.16)个/视野、(12.51±1.56)个/视野;血管数/肌束数分别为0.66±0.05,0.83±0.11,0.90±0.13;肌浆中VEGF质量分数[每克肌肉中VEGF因子的质量(ng)]分别为0.22±0.05,0.30±0.07,0.31±0.08;糖尿病内皮祖细胞移植治疗组与糖尿病PBS对照组比较,毛细血管密度、血管数/肌束数、VEGF值差异均有显著性意义,P<0.05。结论EPC移植能有效治疗糖尿病兔下肢缺血。     

外周血来源的间充质干细胞与内皮祖细胞体外构建血管化组织的研究

目的利用两种外周血细胞在体外构建出血管样组织。方法从外周血提取内皮祖细胞与间充质干细胞并鉴定,在纤维蛋白凝胶中以不同的密度培养,在显微镜下观察至第7天。结果兔外周血可以提取出内皮祖细胞与间充质干细胞,内皮祖细胞与间充质干细胞的比值为100万/m L:200万/m L时可以在体外形成血管样结构。结论外周血中可以提取出特定细胞并在体外共培养形成血管样组织。