血管新生的治疗性应用研究进展

血管成形术和旁路手术治疗,是动脉硬化性疾病的主要干预方法,然而术后血管的再狭窄以及旁路移植物再闭塞限制了其应用,而这些治疗手段对那些动脉病变程度严重且范围广泛的病例并不适用.血管新生,是机体对缺血的生物学反应,可以提供侧支循环改善缺血,被称为闭塞性血管疾病的"生物搭桥术"或"分子搭桥术".对各种生长因子作用的了解是血管新生疗法的基础.治疗性血管生成(therapeutic angiogenesis)可以导致毛细血管的芽生(angiogenesis,血管新生)和侧支血管的发展(arteriogenesis,动脉生成),是动脉闭塞性疾病改善缺血损伤的治疗选择.大量研究表明,通过使用重组生长因子和编码生长因子的基因治疗,可有效改善侧支循环,增加缺血组织的血流量.目前用于治疗性血管生成研究的生长因子主要是血管内皮细胞生长因子(vascular endothelial growth factor,VEGF)及碱性成纤维细胞生长因子(basic fibroblast grouth factor,bFGF).     

超声微泡在缺血性血管疾病诊断与治疗中的研究进展

微泡造影剂受一定强度超声辐照后会破裂并产生声致孔效应,从而使局部毛细血管破裂,血管内容物外渗并在局部引起炎症反应,其产生的炎症因子可促进局部组织血管新生.超声介导微泡造影剂携药物或基因进行缺血性疾病的治疗是一种新型安全有效的靶向治疗技术.本文就超声微泡促进血管新生机制及其在缺血性血管疾病诊断与治疗方面的研究进展作一综述.     

内皮祖细胞在血管新生治疗中的作用

目前对缺血性心脏病研究的一个热点是如何促进缺血部位的新生血管形成,以改善局部的血供情况。促进血管新生(Neovascularization)又包括二个方面,血管形成(angiogene-sis)和血管生成(vascularization)。以往的研究多集中在对影响血管生长的分子调控机制上,近年来,随着对内皮祖细胞(endothelial progenitor cells,EPCs)研究的兴起,人们开始关注EPCs在血管新生中的作用及可能的治疗价值。本文就EPCs与血管新生治疗关系做一综述。1血管新生的过程机体内的血管新生主要包括二种方式:血管形成和血管生成。前者指由已经存在的血管成熟内皮细胞…     

角膜新生血管的发生与治疗

背景:角膜新生血管是国内较常见的致盲眼病之一,但至今尚无特效药物以及特效的治疗方法.目的:全面了解角膜新生血管的发病机制,归纳各种针对角膜血管疾病的治疗方法.方法:电子检索PubMed数据库和中国知识资源总库(CNKI)1989/2009收录的有关角膜新生血管的发病机制及治疗方法的随机对照或半随机对照实验,分析角膜新生发病因素和目前主要的治疗方法及效果.结果与结论:共纳入27个研究,角膜新生血管能损伤患者视力,角膜水肿、血管因子、炎症反应、缺氧、角膜神经等均可能引起角膜新生血管的发生,阿瓦斯汀、脱氧核酶、小干扰RNA、光动力疗法、中药等对角膜新生血管的发生有一定的抑制作用,目前已处于临床或动物实验研究阶段.且随着技术的发展,针对角膜新生血管的治疗技术将更加安全有效.     

间充质干细胞促血管新生的研究进展

间充质干细胞(MSC)具有重要的组织修复和再生的生物学特性,其具有促进血管新生的能力,已被广泛应用于缺血性疾病等的治疗。MSC促进血管新生的机制与促血管生长因子分泌及外泌体的生成有关。在低氧环境下,MSC促血管能力更强,其中,miRNA起到了重要的介导调控作用。本文综述了MSC治疗缺血性疾病的概况及促血管新生机制的研究新进展,重点探讨了低氧和miRNA对MSC促血管新生能力的调控。     

造血干细胞治疗血管性疾病基础与临床应用研究

血管性疾病,尤其是外周血管缺血性疾病的治疗是临床工作者非常棘手的问题。本文就近年来血管新生研究进展,促进血管新生,改善缺血肢体的血液供应的自体造血干细胞移植进行阐述。     

组织构建过程中的运动效应③：本刊中文部

6大鼠缺血下肢微血管生成与运动训练 梅燕（泸州医学院附属医院手麻科，四川省泸州市646000） 推荐理由：运动训练可以改善患者缺血下肢血供，增加无痛行走距离和最大行走距离，改善生存质量。目前人们开始应用血管生长因子及其基因疗方法来促进缺血组织的血管新生已达到治疗缺血性疾病的目的。有研究表明运动锻炼能够促进血管新生，这就为该类疾病提供了新的治疗思路。     

自体血管内皮祖细胞治疗缺血缺氧性脑损伤

背景：缺血缺氧性脑损伤后的神经再生、神经功能的恢复与缺血部位新生血管的形成和重塑有着密切的关系。血管内皮祖细胞参与出生后缺血组织的血管新生及修复,促使血液循环再通和氧气等营养物质的供应,为神经功能的恢复提供微环境。目的：探讨自体血管内皮祖细胞治疗缺血缺氧性脑损伤的可行性、有效性及安全性,探索改善脑损伤患者神经功能修复的新方法。方法：应用计算机检索PubMed、ScienceDirect、Springerlink、CNKI、万方等数据库近10年的相关文献。英文关键词为“EPCs、endothelialprogenitorcell、stroke”等,中文关键词为“内皮祖细胞、干细胞移植、脑卒中”等,选择内容与血管内皮祖细胞治疗缺血缺氧性疾病相关的文献,同一领域文献则选近期发表的或发表在权威杂志上的文章,共纳入43篇参考文献。结果与结论：脑缺血后神经再生、神经功能的恢复与缺血部位新生血管的形成和重塑有着密切的关系,内皮祖细胞参与出生后缺血组织的血管发生及修复,促进血液循环及氧气等营养物质的供应,为神经功能的恢复提供微环境。自体血管内皮祖细胞治疗缺血缺氧性脑损伤是可行的、安全的、有效的,但仍需大量的生物学及动物实验为其临床应用提供客观的理论依据。     

血管生成素样蛋白调控缺血性视网膜病变血管生成及血管通透性的作用研究

血管生成素样蛋白（ANGPTLs）是一类结构类似于血管生成素的分泌型糖蛋白,其家族包括8个成员。ANGPTLs与血管生成素同样具备调节血管生成及血管通透性的能力,却不能与血管生成素特异性受体（Tie1或Tie2）结合,提示ANGPTLs可能通过不同的机制及通路在机体中发挥作用。缺血性视网膜病变（IR）是一组严重影响视力健康的疾病,由不成熟视网膜脉管系统或成熟的视网膜血管损伤造成视网膜缺血,进而导致视网膜血管渗漏或新生血管形成而引起,近年研究发现ANGPTL家族部分成员与IR新生血管形成及血管渗漏有关,提出将其中某些成员作为IR潜在治疗靶标。本综述的目的是描述ANGPTLs在IR中对血管生成及血管通透性的作用及参与其中的分子机制,为相关因子作为IR的潜在治疗靶标提供有用信息。     

糖现视网膜病变的成因和治疗

糖尿病视网膜病变 (diabetic retinopathy,DR)是因微小血管闭塞、缺血 ,以血管新生为主体的增殖性病变。大量的报道指出 ,DR的最重要原因是高血糖 [1 ] ,与其它并发症一样 ,是伴随高血糖而细胞因子、代谢、血流动态异常的一组病症。严重 DR90 %可致盲。现就 DR的成因和治疗作一综述。1　 DR的成因1.1　从细胞因子异常来看 DR的成因　 DR时可见各种细胞因子异常 ,并相互影响 ,主要有下述因子。1. 1. 1　血管内皮增殖因子 (vascular endothelial growthfactor,VEGF)　缺血网膜能产生诱导血管新生的因子 ,主要是 VEGF[2 ] 。由于血管…     

骨髓间充质干细胞移植联合基因治疗缺血性脑血管病

背景：骨髓间充质干细胞移植后是否向神经细胞定向分化,不仅受细胞自身基因调控,更取决于所处外环境中各种信号的影响。目的：就骨髓间充质干细胞的生物学特性、转基因治疗缺血性脑血管病的理论依据以及动物实验和临床研究进展进行综述。方法：由第一作者应用计算机检索PubMed数据库2006年1月至2011年12月及中国期刊网全文数据库2006年1月至2011年12月有关骨髓间充质干细胞生物学特性、转基因治疗缺血性脑血管病的理论依据以及相关动物实验和临床研究的文章,英文检索词为＂Bone Marrow Mesenchymal Stem Cells（BMSCs）transplant,Gene therapy,Ischemic Cerebrovascular Disease（ICD）＂,中文检索词为＂骨髓间充质干细胞移植,基因治疗,缺血性脑血管病＂。排除重复性研究及Meta分析,共保留25篇文献进行综述。结果与结论：对缺血性脑血管病进行细胞移植和基因治疗改善神经功能是目前的研究热点。骨髓间充质干细胞是细胞基因工程治疗的良好载体,转基因培养后能高效地诱导分化为神经细胞,为移植治疗缺血性脑血管病提供细胞源。利用骨髓间充质干细胞移植联合基因治疗缺血性脑血管病已在动物模型上取得了令人瞩目的成就,临床应用还有待于进一步研究,尤其是生物安全性问题仍需进一步探索。     

从缺血性肾病的治疗困惑展望间充质干细胞治疗愿景

慢性肾动脉狭窄引起的缺血性肾脏疾病可能导致肾功能不可逆转的丧失,因其发病率和病死率呈上升趋势,有关临床和基础研究日益受到重视。慢性缺血性肾病的病理生理学是多方面的,涉及复杂的激素免疫和细胞的相互作用,并导致肾脏多种细胞类型损害,而且往往抵抗常规疗法。近年来多中心临床研究证明血管内支架治疗动脉粥样硬化引起的慢性肾动脉狭窄对血压控制,肾功能和预后均无显著益处。因此,有必要寻找新颖的方法来修复肾实质和保护肾脏功能。间充质干细胞(mesenchymal stem cells,MSC)通过旁分泌或内分泌作用赋予肾脏保护,并在一定程度上可直接转化为肾脏细胞,其抗炎和免疫调节性能作用于缺血性肾脏病致病机理的多个环节。本文就利用MSC预防治疗缺血性肾损伤的最新进展作一述评。     

Therapeutic angiogenesis for myocardial ischemia

Therapeutic angiogenesis offers promise as a novel treatment for ischemic heart disease, particularly for patients who are not candidates for current methods of revascularization. The goal of treatment is both relief of symptoms of coronary artery disease and improvement of cardiac function by increasing perfusion to the ischemic region. Protein-based therapy with cytokines including vascular endothelial growth factor and fibroblast growth factor demonstrated functionally significant angiogenesis in several animal models. However, clinical trials have yielded largely disappointing results. The attenuated angiogenic response seen in clinical trials of patients with coronary artery disease may be due to multiple factors including endothelial dysfunction, particularly in the context of advanced atherosclerotic disease and associated comorbid conditions, regimens of single agents, as well as inefficiencies of current delivery methods. Gene therapy has several advantages over protein therapy and recent advances in gene transfer techniques have improved the feasibility of this approach. The safety and tolerability of therapeutic angiogenesis by gene transfer has been demonstrated in phase I clinical trials. The utility of therapeutic angiogenesis by gene transfer as a treatment option for ischemic cardiovascular disease will be determined by adequately powered, randomized, placebo-controlled Phase II and III clinical trials. Cell-based therapies offer yet another approach to therapeutic angiogenesis. Although it is a promising therapeutic strategy, additional preclinical studies are warranted to determine the optimal cell type to be administered, as well as the optimal delivery method. It is likely the optimal treatment will involve multiple agents as angiogenesis is a complex process involving a large cascade of cytokines, as well as cells and extracellular matrix, and administration of a single factor may be insufficient. The promise of therapeutic angiogenesis as a novel treatment for no-option patients should be approached with cautious optimism as the field progresses.     

基因修饰干细胞治疗缺血性心脏病的现状与前景

背景：基因技术联合干细胞植入治疗缺血性心脏病是继单纯干细胞治疗后的一大热点.目的：归纳总结基因修饰及干细胞治疗缺血性心脏病的研究现状.方法：计算机检索PubMed数据库中2000-01/2010-12期间相关文献,检索词为 ＂genetic,stem cells,myocardial infarction＂.选择与基因修饰联合干细胞治疗缺血性心脏病密切相关的的29篇文献进行综述.结果与结论：不同功能的基因对干细胞和/或周围环境进行修饰,改善干细胞及相应的性状,以提高移植干细胞的存活能力、促进缺血心肌及周围的血管新生、改善血管顺应性、增加与宿主心肌细胞的耦联、增强干细胞趋化归巢作用等,提高干细胞治疗缺血性心脏病的效果.随着基因技术与干细胞应用的不断发展,可能在缺血性心脏的临床治疗方面得到广泛的应用.     

Hepatocyte growth factor as potential cardiovascular therapy

Hepatocyte growth factor is a mesenchyme-derived pleiotropic factor that regulates the growth, motility and morphogenesis of various types of cells, and is also a member of the angiogenic growth factors. Hepatocyte growth factor is secreted by vascular endothelial cells and smooth muscle cells, and the hepatocyte growth factor receptor, c-met, was also observed in these vascular cells. Treatment of human aortic endothelial cells with recombinant hepatocyte growth factor resulted in a significant increase in cell proliferation, accompanied by mitogen-activated protein kinase and Akt/protein kinase B phosphorylation. Recently, a novel therapeutic strategy for ischemic diseases using angiogenic growth factors to augment collateral artery development has been proposed. As preclinical study of gene therapy using hepatocyte growth factor to treat peripheral arterial disease, naked hepatocyte growth factor plasmid was intramuscularly injected into the ischemic hind limb of rabbits in order to evaluate its angiogenic activity. Intramuscular injection of hepatocyte growth factor plasmid once on day 10 following surgery, produced significant augmentation of collateral vessel development in the ischemic limb on day 30. In the clinical setting, the authors further investigated the safety and efficacy of hepatocyte growth factor plasmid DNA in patients with critical limb ischemia, in a prospective open-labeled trial. Intramuscular injection of naked plasmid DNA was performed in the ischemic limbs of six patients with critical limb ischemia with arteriosclerosis obliterans (n = 3) or Buerger disease (n = 3) graded as Fontaine III or IV. In the efficacy evaluation, a reduction of pain scale of more than 1 cm on a visual analog pain scale was observed in five out of six patients. An increase in ankle pressure index of more than 0.1 was observed in five out of five patients. The long diameter of eight out of 11 ischemic ulcers in four patients was reduced by more than 25%. Intramuscular injection of naked hepatocyte growth factor plasmid is safe, feasible and can achieve successful improvement of ischemic limbs. Although the present data were obtained to demonstrate safety in a Phase I/early Phase II trial, the initial clinical outcome with hepatocyte growth factor gene transfer seems to indicate its usefulness as sole therapy for critical limb ischemia. Randomized placebo-controlled clinical trials of alternative dosing regimens of gene therapy will be required to define the efficiency of this therapy.     

Hepatocyte growth factor as potential cardiovascular therapy

Hepatocyte growth factor is a mesenchyme-derived pleiotropic factor that regulates the growth, motility and morphogenesis of various types of cells, and is also a member of the angiogenic growth factors. Hepatocyte growth factor is secreted by vascular endothelial cells and smooth muscle cells, and the hepatocyte growth factor receptor, c-met, was also observed in these vascular cells. Treatment of human aortic endothelial cells with recombinant hepatocyte growth factor resulted in a significant increase in cell proliferation, accompanied by mitogen-activated protein kinase and Akt/protein kinase B phosphorylation. Recently, a novel therapeutic strategy for ischemic diseases using angiogenic growth factors to augment collateral artery development has been proposed. As preclinical study of gene therapy using hepatocyte growth factor to treat peripheral arterial disease, naked hepatocyte growth factor plasmid was intramuscularly injected into the ischemic hind limb of rabbits in order to evaluate its angiogenic activity. Intramuscular injection of hepatocyte growth factor plasmid once on day 10 following surgery, produced significant augmentation of collateral vessel development in the ischemic limb on day 30. In the clinical setting, the authors further investigated the safety and efficacy of hepatocyte growth factor plasmid DNA in patients with critical limb ischemia, in a prospective open-labeled trial. Intramuscular injection of naked plasmid DNA was performed in the ischemic limbs of six patients with critical limb ischemia with arteriosclerosis obliterans (n = 3) or Buerger disease (n = 3) graded as Fontaine III or IV. In the efficacy evaluation, a reduction of pain scale of more than 1 cm on a visual analog pain scale was observed in five out of six patients. An increase in ankle pressure index of more than 0.1 was observed in five out of five patients. The long diameter of eight out of 11 ischemic ulcers in four patients was reduced by more than 25%. Intramuscular injection of naked hepatocyte growth factor plasmid is safe, feasible and can achieve successful improvement of ischemic limbs. Although the present data were obtained to demonstrate safety in a Phase I/early Phase II trial, the initial clinical outcome with hepatocyte growth factor gene transfer seems to indicate its usefulness as sole therapy for critical limb ischemia. Randomized placebo-controlled clinical trials of alternative dosing regimens of gene therapy will be required to define the efficiency of this therapy.     

Cellular and molecular therapeutic modalities for arterial obstructive syndromes

Arterial obstructive syndromes result in heart disease, stroke and limb loss, disability, and mortality. Currently available therapeutics for patients with these conditions are inadequate or fail in a significant number of patients. The development of novel therapies for severe coronary arterial disease (CAD), peripheral arterial disease (PAD), and cerebral vascular disease (CVD) is a major goal for modern medicine. Molecular and cell-based therapies for arterial obstructive syndromes have the potential to become clinically useful in the near future. Molecular therapy employs angiogenic proteins and genes in order to initiate the development of new blood vessels that by-pass an arterial occlusion. The induction of a collateral artery system is termed therapeutic angiogenesis or neovascularization. Proteins have been delivered either directly into the ischemic area or via a vector encoding an angiogenic gene. Both protein and gene therapies have been associated with promising preclinical and early phase human trial results in patients with PAD as well as CAD. However, to date, efficacy has not been demonstrated in placebo-controlled, large trails. Today's cell-based therapy is focused on stem cells (SCs) for the treatment of patients after acute myocardial infarction (AMI) or for patients with severe left ventricular dysfunction. Stem cells have shown to increase cardiac performance in uncontrolled, early phase human studies. This improvement is believed to have its origin in myogenesis and neovascularization. In the following review, we will cover current state of molecular- and cellular-based treatments for PAD and CAD that have reached the clinical arena.     

干细胞治疗缺血性心肌病的临床研究进展

缺血性心肌病是影响人类健康的主要疾病之一，采用干细胞移植治疗缺血性心肌病已经成为近年来的研究热点。移植干细胞能够促进新生血管形成和心肌组织再生，减少瘢痕面积，改善心肌收缩能力。目前应用干细胞治疗缺血性心肌病的临床试验所得到的治疗结果不尽相同，不同类型的干细胞来源、注射方法及剂量、随访观察时间均可影响临床治疗效果；干细胞移植所涉及的免疫排斥、促肿瘤形成以及其他潜在的安全性问题仍是医学界重点关注的领域。本文就干细胞移植治疗缺血性心肌病临床研究相关的影响因素及其安全问题进行相关阐述。     

基因修饰干细胞治疗缺血性心脏病的现状与前景

背景:基因技术联合干细胞植入治疗缺血性心脏病是继单纯干细胞治疗后的一大热点.目的:归纳总结基因修饰及干细胞治疗缺血性心脏病的研究现状.方法:计算机检索PubMed数据库中2000-01/2010-12期间相关文献,检索词为 "genetic,stem cells,myocardial infarction".选择与基因修饰联合干细胞治疗缺血性心脏病密切相关的的29篇文献进行综述.结果与结论:不同功能的基因对干细胞和/或周围环境进行修饰,改善干细胞及相应的性状,以提高移植干细胞的存活能力、促进缺血心肌及周围的血管新生、改善血管顺应性、增加与宿主心肌细胞的耦联、增强干细胞趋化归巢作用等,提高干细胞治疗缺血性心脏病的效果.随着基因技术与干细胞应用的不断发展,可能在缺血性心脏的临床治疗方面得到广泛的应用.     

Gene therapy for arteriosclerotic diseases

Recent progress in molecular biology gives us gene therapy, as a new strategy for treatment of cardiovascular diseases. Targeted diseases have been wide-spread from single gene-deficient diseases to more complexed adult diseases such as restenosis after angioplasty and ischemic diseases. Clinical gene therapy for restenosis and angina using VEGF gene have already performed in USA and they can show beneficial effects of such strategies. On the other hand, we have just started a clinical trial using E2F decoy for restenosis after PTA or PTCA, since April 2000. E2F decoy is expected to become a new treatment for restenosis as a gene therapy. Also, the feasibility of a novel therapeutic strategy using angiogenic growth factors such as VEGF to augment collateral artery development has recently entered the realm of treatment of ischemic diseases. We focus on HGF, which is a novel endothelial growth factor. HGF-based therapeutic angiogenesis would possibly result a new treatment for severe ischemic diseases.