EphrinB2/EphB4 在血管生长中的作用及中医药研究展望*

近年来,有关ephrin及其Eph受体的作用研究已从神经系统方面逐步向血管生长扩展。已有研究表明ephrinB2/EphB4及其独特的双向信号转导几乎参与血管生长的每个方面,涉及血管发育过程中的动静脉分化、胚胎后血管新生包括内皮细胞增殖、迁移、粘附和分化等过程,且与VEGF、Notch等血管新生调控因子关系密切。另外,实验表明活血化瘀名方血府逐瘀汤显著的促血管新生作用与ephrinB2/EphB4相关,说明中医药促血管新生中ephrinB2/EphB4具有重要作用。本文部分总结了ephrinB2/EphB4在血管生长中的作用,并提出中医药在这方面的展望。     

心脏可产生一种血管细胞生长抑制因子

心脏可产生一种血管细胞生长抑制因子生理状态下,心肌可产生大量促进细胞分裂、增殖的生长因子,但细胞的更新率很低,没有血管新生。因此推测心肌可能存在生长抑制因子,抵消了生长因子的作用,以维持心脏的正常结构。最近Ｗｅｓｔｅｒｎａｃｈｅｒ等的研究初步证实了这...     

内皮抑素及其在抗肿瘤中的应用

内皮抑素是一种抗血管生成的抑制因子,它特异性地作用于新生微血管的内皮细胞,其水平与肿瘤血管生成有着明显的相关性。体内外的研究均表明,内皮抑素具有无毒副作用、不容易产生耐药性和易达到有效药物浓度等优点。我们简要综述了内皮抑素的特性、作用机制,及其在抗肿瘤应用等方面的研究进展。     

肿瘤干细胞与血管新生的研究进展

肿瘤生长及转移依赖于新生血管的形成,大量研究认为肿瘤干细胞与血管新生之间存在密切联系,肿瘤干细胞可能转分化为内皮细胞参与新生血管生成,并通过分泌促血管生长因子、基质衍生因子和低氧诱导因子参与对血管新生的调控。     

血管内皮生长因子与肿瘤

血管内皮生长因子是新近确定的一种具有旁分泌机制的生长因子,能特异作用于血管内皮细胞,促进其增殖及新生血管的形成,同时还有增加血管通透性的作用．由于其生物学活性与实体瘤的生长密切相关,因此对它的研究倍受关注,进展非常迅速．     

有氧运动与干细胞动员的缺血心脏血管新生研究进展

有氧运动具有明确的血管新生效应,包括缺血心脏,但其机制尚未完全阐明。心肌梗死(MI)后冠脉微血管新生是心脏修复的前提。新近研究表明,血管新生来源于体内干/祖细胞的动员与参与,并以旁分泌效应影响内皮细胞(EC)功能及微血管分布效果,运动可以动员、激活内源性干细胞因子和血管生成因子的表达与分泌,并能从表观遗传学角度影响心脏血管新生。探索不同运动方式及强度对缺血心脏血管新生的作用及其分子机制,对缺血心脏的预防及术后康复具有重要意义。本文从心脏血管新生及其调控机制、自体干细胞动员参与缺血心脏的血管新生和运动通过干细胞动员促进缺血心脏血管新生等方面综述运动促进缺血心脏血管新生的主要机制、存在问题及相关研究进展。     

血管内皮生长因子的神经保护作用

血管内皮生长因子（vascular endothelial growth factor,VEGF）是内皮细胞特异性的生长因子,大多数关于VEGF的研究都是致力于其在血管生长方面的作用,而近年来有大量文献报道VEGF具有神经营养和促神经发生作用,它能够直接作用于神经元细胞和神经胶质细胞甚至是神经干细胞,促进其生长及存活。VEGF的多种功能使其和多种神经退行性疾病相关,如阿茨海默病,肌萎缩侧索硬化症,帕金森病等。导入VEGF基因能够改善肌萎缩侧索硬化症、帕金森病动物模型的病情。     

内皮抑素在新生血管形成相关疾病中的作用机制研究进展

新血管形成是许多生理、病理过程的关键步骤,受血管形成促进因子和抑制因子的调节。内皮抑素是最重要的血管形成抑制因子之一,可在体外抑制血管内皮细胞的增殖、迁移和血管化,在动物模型中抑制新血管形成,对新生血管形成相关疾病,特别是肿瘤有治疗作用。关于内皮抑素抑制新血管形成的分子机制尚无定论,已有线索表明,它可通过与VEGF、MMP-2、整合素以及VEGF受体KDR等相互作用,从而抑制内皮细胞增殖、迁移或通过多种途径促进内皮细胞凋亡。本就内皮抑素作用的分子机制,及其作用于新血管形成相关疾病的最新研究成果进行综述。     

四跨膜超家族蛋白CD151促血管生成的研究进展

利用促血管生成因子促进血管生成已成为当前治疗缺血性疾病研究的一个热点。CD151蛋白作为四跨膜超家族蛋白(transmembrane-4 superfamily proteins,TM4SF)的重要成员之一,其在促血管生成方面起着重要的作用。CD151在体外能促进血管内皮细胞的增值、迁移及管状结构的形成,在体内能增加大鼠缺血后肢和缺血心肌区域的微血管数量,促进血管生成。CD151蛋白作为一个新的促血管生成因子日益受到大家的关注。本文就CD151促血管生成的研究进展进行综述。     

内皮细胞增殖抑制因子研究进展

内皮细胞过度增殖引起的病理性血管生成是肿瘤、类风湿性关节炎等发病的关键环节。内皮细胞增殖由血管内皮细胞生长因子等促血管生成因子提供促增殖信号,而新近发现的多种内皮增殖抑制因子,如血管内皮抑素、血管抑素、血小板反应蛋白-1、微囊蛋白1、某些microRNAs和某些抑癌基因等,则通过抑制促增殖信号、调节细胞周期、诱导细胞凋亡等途径下调内皮细胞的增殖及血管生成。内皮增殖抑制因子可望成为病理性血管生成防治的新靶点。     

Combination of angiopoietin-1 and vascular endothelial growth factor gene therapy enhances arteriogenesis in the ischemic myocardium

We hypothesised that angiopoietin-1 (Ang-1), in conjunction with vascular endothelial growth factor (VEGF) gene therapy, can enhance arteriogenesis and angiogenesis during myocardial ischemia. Mice were given a single intramyocardial injection of saline, phVEGF-A(165) and phAng-1 or a combination thereof into the non-ischemic normal heart or into the ischemic border zone of the infarcted heart. In the normal and the ischemic myocardium, gene transfer of phVEGF-A(165) alone increased the myocardial capillary density by 16% and 36%, respectively, and phAng-1 had a similar effect. In the normal heart, the ratio of arteriolar to capillary densities increased with phVEGF-A(165) and more so in the ischemic myocardium where phAng-1 also had an effect. Furthermore, the combination of plasmids induced an up to 7.5-fold increase. Transient overexpression of VEGF-A(165) boosts endogenous arteriogenesis in addition to capillary angiogenesis. Ang-1 further boosts this effect at the arteriolar level.     

Neovascularization of ischemic myocardium by newly isolated tannins prevents cardiomyocyte apoptosis and improves cardiac function

During remodeling progress post myocardial infarction, the contribution of neoangiogenesis to the infarct-bed capillary is insufficient to support the greater demands of the hypertrophied but viable myocardium resulting in further ischemic injury to the viable cardiomyocytes at risk. Here we reported the bio-assay-guided identification and isolation of angiogenic tannins (angio-T) from Geum japonicum that induced rapid revascularization of infarcted myocardium and promoted survival potential of the viable cardiomyocytes at risk after myocardial infarction. Our results demonstrated that angio-T displayed potent dual effects on up-regulating expression of angiogenic factors, which would contribute to the early revascularization and protection of the cardiomyocytes against further ischemic injury, and inducing antiapoptotic protein expression, which inhibited apoptotic death of cardiomyocytes in the infarcted hearts and limited infarct size. Echocardiographic studies demonstrated that angio-T-induced therapeutic effects on acute infarcted myocardium were accompanied by significant functional improvement by 2 days after infarction. This improvement was sustained for 14 days. These therapeutic properties of angio-T to induce early reconstitution of a blood supply network, prevent apoptotic death of cardiomyocytes at risk, and improve heart function post infarction appear entirely novel and may provide a new dimension for therapeutic angiogenesis medicine for the treatment of ischemic heart diseases.     

Neovascularization and Hematopoietic Stem Cells

Vasculogenesis and angiogenesis are the major forms of blood vessel formation. Angiogenesis is the process where new vessels grow from pre-existing blood vessels, and is very important in the functional recovery of pathological conditions, such as wound healing and ischemic heart diseases. The development of better animal model and imaging technologies in past decades has greatly enriched our understanding on vasculogenesis and angiogenesis processes. Hypoxia turned out to be an important driving force for angiogenesis in various ischemic conditions. It stimulates expression of many growth factors like vascular endothelial growth factor, platelet-derived growth factor, insulin-like growth factor, and fibroblast growth factor, which play critical role in induction of angiogenesis. Other cellular components like monocytes, T cells, neutrophils, and platelets also play significant role in induction and regulation of angiogenesis. Various stem/progenitor cells also being recruited to the ischemic sites play crucial role in the angiogenesis process. Pre-clinical studies showed that stem/progenitor cells with/without combination of growth factors induce neovascularization in the ischemic tissues in various animal models. In this review, we will discuss about the fundamental factors that regulate the angiogenesis process and the use of stem cells as therapeutic regime for the treatment of ischemic diseases.     

Increased cross-bridge cycling rate in stunned myocardium

It is well known that the implantation of bone marrow mononuclear cells (BM-MNCs) into ischemic hearts can induce angiogenesis and improve cardiac function after myocardial infarction, but the precise mechanisms of these actions are unclear. We hypothesize that the cytokines produced by BM-MNCs play a key role in this cell-based therapy. BM-MNCs from rats were cultured under normoxic or hypoxic (1% O2) conditions for 24 h, and then supernatants were collected for study. ELISA and Western blotting analysis showed that various cytokines, including VEGF, IL-1 beta, PDGF, and IGF-1, were produced from BM-MNCs, some of which were enhanced significantly under hypoxia stimulation. When compared with a control blank medium, the supernatants of BM-MNCs cultured under normoxic or hypoxic conditions inhibited apoptosis significantly and preserved the contractile capacity of isolated adult rat cardiomyocytes in vitro (P < 0.05). Using a rat model of acute myocardial infarction, we injected the supernatants of BM-MNCs or control medium intramyocardially on day 0 and then intraperitoneally on days 2, 4, and 6 after infarction. When compared with the control medium, the supernatants of BM-MNCs cultured under both normoxic or hypoxic conditions increased the microvessel density and decreased the fibrotic area in the infarcted myocardium significantly, contributing to remarkable improvement in cardiac function. Various cytokines were produced by BM-MNCs, and these cytokines contributed to functional improvement of the infarcted heart by directly preserving the contractile capacity of the myocardium, inhibiting apoptosis of cardiomyocytes, and inducing therapeutic angiogenesis of the infarcted heart.     

Myocardial angiogenesis

Coronary angiogenesis and collateral growth are chronic adaptations to myocardial ischemia, which are aimed at restoring coronary blood flow and salvaging myocardium in an ischemic region. Although we have assumed that myriad numbers of growth factors are involving in this adaptation, details in the underlying mechanisms, i.e., number of angiogenic factors, angiostatic factors, their receptors/signaling cascades, interactions/crosstalk among the signaling pathways and receptors, and the time course of expression/function of a particular factor or pathway during the successful adaptation are still unclear; they are, probably, harmonized like a symphony. Although there is as of yet no consensus about the mechanisms and causal factors for these cononary adaptations to ischemia, recent evidence strongly suggests that a balance between growth factors and growth inhibitors is critical. In this review we introduce vascular endothelial growth factor, angiopoietins, and angiostatin, as factors playing pivotal roles in coronary angiogenesis and collateral growth.     

Recruitment of stem cells by hepatocyte growth factor via intracoronary gene transfection in the postinfarction heart failure

We aim to study the amelioration effect of adenovirus5-mediated human hepatocyte growth factor gene transfer on postinfarction heart failure in swine model. Twelve Suzhong young swine were randomly divided into 2 groups of 6 pigs each: Ad5-HGF group and mock-vector Ad5 group. Four weeks after ligation of the left anterior descending coronary artery, Ad5-HGF was intracoronarily transferred into the myocardium. Simultaneously, gate cardiac perfusion imaging was performed to evaluate the heart function. Three weeks later, gate cardiac perfusion imaging was performed again, then the hearts were removed and sectioned for immunohistochemical examination to illustrate the effects of Ad5-HGF on infarcted myocardium. The expression of HGF was examined by ELISA. The results were: (1) compared with the mock-vector Ad5 group, high expression of human HGF was observed in the myocardium of Ad5-HGF group; (2) in the Ad5-HGF group, the number of CD117 cells co-expressing c-Met per mm2 was significantly larger; (3) the improvement in LVEF was greater in the Ad5-HGF group than in the mock-vector Ad5 group. We concluded that: (1) high expression of human HGF was observed in the myocardium through intracoronary gene transfection; (2) HGF can improve the mobilization of CD117 /c-Met stem cells into ischemic myocardium. The amelioration effect of HGF on postinfarction heart failure could not be limited to stimulating angiogenesis, anti-apoptosis, anti-fibrosis, but was also involved in the recruitment of stem cells into myocardium.     

Myocardial angiogenesis

Coronary angiogenesis and collateral growth are chronic adaptations to myocardial ischemia, which are aimed at restoring coronary blood flow and salvaging myocardium in an ischemic region. Although we have assumed that myriad numbers of growth factors are involving in this adaptation, details in the underlying mechanisms, i.e., number of angiogenic factors, angiostatic factors, their receptors/signaling cascades, interactions/crosstalk among the signaling pathways and receptors, and the time course of expression/function of a particular factor or pathway during the successful adaptation are still unclear; they are, probably, harmonized like a symphony. Although there is as of yet no consensus about the mechanisms and causal factors for these cononary adaptations to ischemia, recent evidence strongly suggests that a balance between growth factors and growth inhibitors is critical. In this review we introduce vascular endothelial growth factor, angiopoietins, and angiostatin, as factors playing pivotal roles in coronary angiogenesis and collateral growth. (Mol Cell Biochem 264: 35–44, 2004)     

Recruitment of stem cells by hepatocyte growth factor via intracoronary gene transfection in the postinfarction heart failure

We aim to study the amelioration effect of adenovirus5-mediated human hepatocyte growth factor gene transfer on postinfarction heart failure in swine model. Twelve Suzhong young swine were randomly divided into 2 groups of 6 pigs each: Ad5-HGF group and mock-vector Ad5 group. Four weeks after ligation of the left anterior descending coronary artery, Ad5-HGF was intracoronarily transferred into the myocardium. Simultaneously, gate cardiac perfusion imaging was performed to evaluate the heart function. Three weeks later, gate cardiac perfusion imaging was performed again, then the hearts were removed and sectioned for immunohistochemical examination to illustrate the effects of Ad5-HGF on infarcted myocardium. The expression of HGF was examined by ELISA. The results were: (1) compared with the mock-vector Ad5 group, high expression of human HGF was observed in the myocardium of Ad5-HGF group; (2) in the Ad5-HGF group, the number of CD117+ cells co-expressing c-Met per mm2 was significantly larger; (3) the improvement in LVEF was greater in the Ad5-HGF group than in the mock-vector Ad5 group. We concluded that: (1) high expression of human HGF was observed in the myocardium through intracoronary gene transfection; (2) HGF can improve the mobilization of CD117+/c-Met+ stem cells into ischemic myocardium. The amelioration effect of HGF on postinfarction heart failure could not be limited to stimulating angiogenesis, anti-apoptosis, anti-fibrosis, but was also involved in the recruitment of stem cells into myocardium.     

The effect of immune cell-derived exosomes in the cardiac tissue repair after myocardial infarction: Molecular mechanisms and pre-clinical evidence

After a myocardial infarction (MI), the inflammatory responses are induced and assist to repair ischaemic injury and restore tissue integrity, but excessive inflammatory processes promote abnormal cardiac remodelling and progress towards heart failure. Thus, a timely resolution of inflammation and a firmly regulated balance between regulatory and inflammatory mechanisms can be helpful. Molecular- and cellular-based approaches modulating immune response post-MI have emerged as a promising therapeutic strategy. Exosomes are essential mediators of cell-to-cell communications, which are effective in modulating immune responses and immune cells following MI, improving the repair process of infarcted myocardium and maintaining ventricular function via the crosstalk among immune cells or between immune cells and myocardial cells. The present review aimed to seek the role of immune cell-secreted exosomes in infarcted myocardium post-MI, together with mechanisms behind their repairing impact on the damaged myocardium. The exosomes we focus on are secreted by classic immune cells including macrophages, dendritic cells, regulatory T cells and CD4⁺ T cells; however, further research is demanded to determine the role of exosomes secreted by other immune cells, such as B cells, neutrophils and mast cells, in infarcted myocardium after MI. This knowledge can assist in the development of future therapeutic strategies, which may benefit MI patients.