内皮祖细胞与低氧性肺动脉高压

低氧性肺动脉高压(HPH)是一种致死性很高的肺血管疾病,其发病与血管内皮的损伤密切相关.近年来研究表明,内皮祖细胞(EPCs)在HPH血管内皮修复中具有重要作用.本文总结了近年来EPCs动员、归巢的分子生物学研究进展.研究了EPCs在HPH发生、发展中的作用,以及药物和EPCs移植对HPH的影响.     

缺氧对糖尿病血管内皮祖细胞的影响

血管内皮的损害和再生对维持血管的完整性十分重要,血循环中骨髓来源的血管内皮祖细胞有助于血管内皮的修复.局部缺血后,血管内皮祖细胞从骨髓动员到血液中,然后归巢到缺血组织处,在缺血处通过旁分泌生长因子或者渗入血管来促进新生血管形成.糖尿病患者的血管内皮祖细胞在缺氧条件下,功能受到损害,包括动员、附着、迁移、增殖等一系列环节...     

内皮祖细胞在肺动脉高压的作用

内皮祖细胞是成熟血管内皮细胞的前体细胞,属于干细胞群体,其在血管再生与修复方面的应用越来越受到关注.肺动脉高压作为一种致死性很高的肺血管疾病,其发病与血管内皮损伤密切相关.目前的研究证实,内皮祖细胞在肺动脉高压血管内皮修复中具有重要作用,内皮祖细胞移植有可能成为临床治疗肺动脉高压的一种有效手段.     

SDF-1/CXCR-4对内皮祖细胞生物学功能的影响

内皮祖细胞（EPC）移植或动员内源性EPC可加速损伤血管的再内皮化。基质细胞衍生因子-1（SDF-1）能通过其受体CXCR4促进骨髓干细胞向EPC方向分化,抑制EPC凋亡。升高外周血SDF-1浓度可动员EPC进入外周血。SDF-1/CXCR4系统在EPC迁移、捕获及归巢过程中起重要作用,参与促进缺血性血管生成。     

内皮祖细胞信号通路调控

血管内皮受到损伤后,骨髓来源的内皮祖细胞(endothelial progenitor cells,EPC)能够被动员到外周循环血液中,归巢到缺血区域或者血管损伤部位,诱导内皮细胞增殖、迁移或者自己分化为功能性内皮细胞,促进受损血管的再内皮化.因此其有望成为治疗心血管疾病的一种新的工具.然而,调控内皮祖细胞增殖、迁移、分化等生物学特性的信号通路的研究还有待深入,它既是该领域的难点,也是热点,文章就调控内皮祖细胞信号通路的研究做一综述.     

内皮祖细胞移植对肺动脉高压大鼠血流动力学及肺血管结构的影响

目的 探讨大鼠内皮祖细胞(EPC)移植对野百合碱(MCT)所致大鼠肺动脉高压(PAH)的血流动力学及肺血管结构的影响.方法 体外培养,鉴定EPCs.用MCT诱发的PAH模型组(n=11)大鼠,由尾静脉注入标记的EPC,移植第21天测定肺血流动力学参数,计算平均肺动脉压(MPAP),右心指数.观察EPCs移植后分化为血管内皮细胞的能力及肺血管结构变化.结果 移植EPC 3周后,荧光显微镜观察部分标记的EPCs分化为血管内皮细胞.与模型组相比,EPC治疗组(n=10)MPAP明显下降[(25.9±0.7)比(29.35±2.2)mmHg,P<0.05],右心指数明显下降(0.43±0.04比0.49±0.05,P<0.05),肺小动脉厚度指数[WT%:(17.7±3.8)%比(29.8±4.3)%]和面积指数[WA%:(54.6±3.9)%比(74.8±4.5)%]明显下降(P均<0.05).结论 同种异体EPC移植可有效降低肺动脉压力,肺动脉血管壁厚度指标和面积指数,改善右心肥厚.作用机制尚需进一步研究.     

内皮祖细胞与缺血性脑血管病的细胞治疗

内皮祖细胞(EPC)是血管内皮细胞的前体细胞,存在于骨髓、外周血和脐血中,并参与出生后的血管发生过程.内源性和外源性因素刺激可动员骨髓EPC进入外周血,参与缺血组织的血管重建和损伤血管的再内皮化过程.血液循环中的EPC数量或质量下降是缺血性卒中预后不良的重要原因之一.EPC移植有可能为缺血性脑血管病的治疗提供一种全新的治疗策略.     

血管内皮生长因子与肺部疾病的关系

血管内皮生长因子是作用于血管内皮细胞的重要血管调节因子,它通过与内皮上的特异受体结合,发挥促进内皮细胞增殖、分化、诱导血管生成、增加微血管通透性等多种功能。近年研究显示血管内皮生长因子在慢性阻塞性肺疾病、肺动脉高压、急性肺损伤、肺癌等疾病发病中起到了重要作用。本文就血管内皮生长因子在慢性阻塞性肺疾病、肺动脉高压、急性肺损伤、肺癌等疾病中的作用综述如下。     

内皮祖细胞移植对肺动脉高压大鼠血流动力学及肺血管结构的影响

目的探讨大鼠内皮祖细胞(EPC)移植对野百合碱(MCT)所致大鼠肺动脉高压(PAH)的血流动力学及肺血管结构的影响。方法体外培养,鉴定 EPCs。用 MCT 诱发的 PAH 模型组(n=11)大鼠,由尾静脉注入标记的 EPC,移植第21天测定肺血流动力学参数,计算平均肺动脉压(MPAP),右心指数。观察 EPCs 移植后分化为血管内皮细胞的能力及肺血管结构变化。结果移植 EPC 3周后,荧光显微镜观察部分标记的 EPCs 分化为血管内皮细胞。与模型组相比,EPC 治疗组(n=10)MPAP 明显下降[(25.9±0.7)比(29.3±2.2)mmHg,P<0.05],右心指数明显下降(0.43±0.04比0.49±0.05,P<0.05),肺小动脉厚度指数[WT%:(17.7±3.8)%比(29.8±4.3)%]和面积指数[WA%:(54.6±3.9)%比(74.8±4.5)%]明显下降(P 均<0.05)。结论同种异体 EPC 移植可有效降低肺动脉压力,肺动脉血管壁厚度指标和面积指数,改善右心肥厚。作用机制尚需进一步研究。     

循环内皮祖细胞在肺动脉高压形成中的作用及治疗学应用前景

近年来,内皮祖细胞在肺动脉高压(pulmonary arterial hypertension,PAH)形成中的作用越来越受到学术界重视,基于内皮祖细胞移植治疗PAH的报道也逐年增多.内皮祖细胞存在于骨髓、大动脉血管外膜或循环血液中,在肺动脉内皮损伤的情况下可在损伤部位增殖分化为成熟的内皮细胞,进而通过重建正常的肺血管内皮结构和功能达到治疗PAH的效果.本文对循环内皮祖细胞在PAH形成中的作用及其应用前景作一综述.     

Endothelial progenitor cells: Quo Vadis?

The term endothelial progenitor cell (EPC) was coined to refer to circulating cells that displayed the ability to display cell surface antigens similar to endothelial cells in vitro, to circulate and lodge in areas of ischemia or vascular injury, and to facilitate the repair of damaged blood vessels or augment development of new vessels as needed by a tissue. More than 10 years after the first report, the term EPC is used to refer to a host of circulating cells that display some or all of the qualities indicated above, however, essentially all of the cells are now known to be members of the hematopoietic lineage. The exception is a rare viable circulating endothelial cell with clonal proliferative potential that displays the ability to spontaneously form inosculating human blood vessels upon implantation into immunodeficient murine host tissues. This paper will review the current lineage relationships among all the cells called EPC and will propose that the term EPC be retired and that each of the circulating cell subsets be referred to according to the terms already existent for each subset. This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited".     

Notch信号通路与肺动脉高压

肺动脉高压( pulmonary hypertension,PH)时,参与肺血管重塑的内皮细胞、平滑肌细胞等存在不同程度的Notch家族基因表达上调.Notch信号转导通路在肺血管形成,血管平滑肌细胞及内皮细胞等增殖、分化、凋亡方面起重要调控作用.Notch信号转导通路参与PH形成和发展.这为PH的治疗提供了前景广阔的...     

Circulating endothelial progenitor cells correlate with erectile function in patients with coronary heart disease.

AIMS: The aim of the study was to determine the influence of endothelial progenitor cells (EPC) on erectile dysfunction (ED). EPC play a major role in repair mechanisms of the endothelial monolayer, but the role of EPC in ED is unclear. METHODS AND RESULTS: Circulating levels of CD34(+)/KDR(+) and CD133(+) EPC were determined in 119 patients with known coronary artery disease. ED was evaluated with an ED-score generated from the KEED questionnaire. Prevalence of ED was 59.7%. In univariate analysis, age, hypertension, reduced left ventricular ejection fraction (LVEF), diabetes, and circulating levels of CD133(+) EPC, but not cardiovascular drug treatment were associated with ED. Body mass index (BMI) was positively (r = 0.319, P=0.003) and high-density lipoprotein was negatively (r=-0.246, P=0.034) correlated with ED. Adjustment for age, diabetes, hypertension, BMI, smoking, LVEF, use of statins and lower urinary tract symptoms, and prior coronary intervention revealed low levels of circulating immature CD133(+) EPC as independent risk factor for ED (95% CI -11.183 to -1.7371, P=0.008). CONCLUSION: Reduced levels of circulating CD133(+) EPC are an independent risk factor for ED. Thus, EPC may be a link between cardiovascular risk factors, endothelial dysfunction, and ED.     

Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization.

AIMS: Erythropoietin (EPO) improves cardiac function and induces neovascularization in chronic heart failure (CHF), although the exact mechanism has not been elucidated. We studied the effects of EPO on homing and incorporation of endothelial progenitor cells (EPC) into the myocardial microvasculature and myocardial expression of angiogenic factors. METHODS AND RESULTS: CHF was induced in rats by coronary artery ligation resulting in myocardial infarction (MI) after bone marrow had been replaced by human placental alkaline phosphatase (hPAP) transgenic cells. We studied the effects of darbepoetin alfa treatment (EPO, 40 microg/kg, every 3 weeks, starting 3 weeks after MI) on longitudinal changes in left ventricular (LV) function, circulating EPC, myocardial histology, and expression of vascular endothelial growth factor (VEGF) determined 9 weeks after MI. EPO prevented LV-dilatation and improved cardiac function (all P < 0.05), which was associated with 42% increased capillary growth (P < 0.01). EPO-induced mobilization of EPC from the bone marrow (P < 0.01), which resulted in a three-fold increased homing of EPC into the cardiac microvasculature. The percentage of the endothelium that consisted of bone marrow derived cells was significantly increased (3.9 +/- 0.5 vs. 11.4 +/- 1%, P < 0.001) comprising 30% of the newly formed capillaries. In addition, EPO treatment resulted in a 4.5-fold increased myocardial expression of VEGF, which correlated strongly with neovascularization (r = 0.67; P < 0.001). VEGF was equally expressed by endothelial cells of myocardial and bone marrow origin. CONCLUSION: EPO-induced neovascularization in post-MI heart failure is mediated through a combination of EPC recruitment from the bone marrow and increased myocardial expression of VEGF.     

Globular adiponectin improves high glucose-suppressed endothelial progenitor cell function through endothelial nitric oxide synthase dependent mechanisms

Plasma levels of adiponectin, an adipose-specific protein with putative anti-atherogenic properties, could be down-regulated in obese and diabetic subjects. Recent insights suggest that the injured endothelial monolayer is regenerated by circulating endothelial progenitor cells (EPCs), but high glucose reduces number and functions of EPCs. Here, we tested the hypothesis that globular adiponectin can improve high glucose-suppressed EPC functions by restoration of endothelial nitric oxide synthase (eNOS) activity. Late EPCs isolated from healthy subjects appeared with cobblestone shape at 2-4 weeks. EPCs were incubated with high glucose (25 mM) and treatment with globular adiponectin for functional study. Migration and tube formation assays were used to evaluate the vasculogenetic capacity of EPCs. The activities of eNOS, Akt and concentrations of nitric oxide (NO) were also determined. Administration of globular adiponectin at physiological concentrations promoted EPC migration and tube formation, and dose-dependently upregulated phosphorylation of eNOS, Akt and augmented NO production. Chronic incubation of EPCs in high-glucose medium significantly impaired EPC function and induced cellular senescence, but these suppression effects were reversed by treatment with globular adiponectin. Globular adiponectin reversed high glucose-impaired EPC functions through NO- and p38 MAPK-related mechanisms. In addition, nude mice that received EPCs treated with adiponectin in high glucose medium showed a significant improvement in blood flow than those received normal saline and EPCs incubated in high glucose conditions. The administration of globular adiponectin improved high glucose-impaired EPC functions in vasculogenesis by restoration of eNOS activity. These beneficial effects may provide some novel rational to the vascular protective properties of adiponectin.     

Long-term beneficial effects of statins on vascular manifestations in patients with systemic sclerosis

Abstract

We conducted a 24-month, open-label trial to evaluate the long-term effects of statins on vascular symptoms in patients with systemic sclerosis (SSc). Ten patients received 10 mg/day atorvastatin, but two dropped out to treat other organ involvement. Raynaud’s phenomenon, global measures of health, and psychological scales were assessed in addition to circulating angiogenic factors and endothelial activation/injury markers in eight patients at 0 (pretreatment), 1, 3, 12, and 24 months of treatment. Circulating endothelial progenitor cells (EPCs) were serially quantified by cell sorting and three-color flow cytometry. There were no adverse events. Raynaud’s phenomenon improved during atorvastatin treatment, with significant reductions in the Raynaud’s Condition Score (P = 0.01) and the patient assessment by visual analog scale (P = 0.0003). SSc-associated upregulation of angiogenic factors and vascular endothelial activation/injury markers were reduced (P < 0.01 for all comparisons). Improvement in these parameters was best at 12 and 24 months of treatment. The EPC number was increased at 1 month of treatment (P < 0.01), but soon dropped below baseline. This pilot study suggests that statins may be beneficial in treating vascular manifestations of SSc, through their pleiotropic effects. However, this treatment did not correct the defect in EPC recruitment.     

Endothelial progenitor cells for the treatment of diabetic vasculopathy: panacea or Pandora’s box?

The discovery of endothelial progenitor cell (EPC) a decade ago has refuted the previous belief that vasculogenesis only occurs during embryogenesis. The reduced circulating concentration of EPCs is a surrogate marker of endothelial function and has been implicated in the pathogenesis of many vascular diseases. To date, the therapeutic benefit of neovascularization in ischaemic conditions in a non-diabetic setting has been demonstrated. This article aims to review the biology of EPCs in the diabetic setting with special emphasis on the effects of cardiovascular risk factor modification on EPC phenotype and methods to reverse or augment EPC dysfunction. The potential of the use of EPCs in the treatment of the diabetic vascular dysfunction will also be discussed.