内皮祖细胞与PI3K/Akt信号传导通路

内皮祖细胞作为内皮的前体细胞,主要来源于骨髓,在成人受损血管的修复、新生血管发生/生成中起重要作用.多种伴有血管内皮细胞损伤的疾病都可引起外周血循环、内皮祖细胞数量、功能的变化.因此,内皮祖细胞功能的研究,日益为人们所关注.研究显示PI3K/Akt信号传导通路在内皮祖细胞的动员、迁移、归巢、分化、抗凋亡上发挥重要作用.现主要就内皮祖细胞与PI3K/Akt信号传导通路关系作一综述.     

Notch信号通路在血管生成中的作用研究进展

血管生成存在于机体生长发育的各个阶段.Notch信号是细胞间相互作用的重要信使,大量的研究发现Notch信号在细胞分化及血管生成方面发挥重要的调控作用.Notch信号参与生理性血管生成可能与以下机制有关:调节尖细胞与茎细胞的分化,调节动静脉分化、内皮祖细胞、血管壁细胞、血管内皮生长因子、一氧化氮以及与其他信号通路相互作用.此外,Notch信号在肿瘤以及损伤后组织修复等病理性血管生成中亦发挥重要作用.明确Notch信号的作用机制对疾病的治疗有重要意义.     

血管内皮祖细胞及其在肿瘤中的作用

血管内皮祖细胞是一类能够迁移、增殖,并分化为成熟血管内皮细胞的前体细胞.它们不仅参与胚胎发育过程的血管发生及血管新生,与出生后的血管发生及血管新生也有密切关系.血管内皮祖细胞参与肿瘤血管新生,而肿瘤新生血管系统对肿瘤发生、发展及转移起关键作用,本文对血管内皮祖细胞及其在肿瘤发生和治疗中的作用进行综述.     

GTP环化水解酶I/四氢生物蝶呤通路对高血压内皮祖细胞体外活性和体内再内皮化能力的调节

目的研究GTP环化水解酶Ⅰ/四氢生物蝶呤信号通路对高血压患者循环内皮祖细胞功能的调节。方法分别纳入高血压患者和健康志愿者各19例,采集外周血进行内皮祖细胞分离、培养及鉴定,评估其迁移、增殖、黏附活性;建立裸鼠动脉损伤模型并移植高血压患者和健康志愿者内皮祖细胞,评估内皮祖细胞修复损伤血管内皮功能,并检测内皮祖细胞GTP环化水解酶Ⅰ/四氢生物蝶呤通路及一氧化氮、环磷酸鸟苷、凝血酶敏感蛋白1的mRNA表达水平。通过基因干扰、基因转染或药物阻滞干预,进一步证实该信号通路对内皮祖细胞功能的调节作用。结果高血压患者内皮祖细胞体外活性及体内再内皮化功能降低,且内皮祖细胞GTP环化水解酶Ⅰ/四氢生物蝶呤通路及其下游信号分子一氧化氮、环磷酸鸟苷的mRNA表达水平亦下降,而凝血酶敏感蛋白1 mRNA表达水平则升高。抑制该信号通路的表达可削弱内皮祖细胞的体外活性及再内皮化功能。结论研究证实GTP环化水解酶I/四氢生物蝶呤通路可通过凝血酶敏感蛋白1及可溶性鸟苷酸环化酶/环磷酸鸟苷系统调节高血压患者内皮祖细胞的体外及体内功能。     

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.     

骨髓血管内皮祖细胞的分离培养及分化鉴定

目的 研究分离、培养小鼠骨髓血管内皮祖细胞的方法并对其进行诱导分化鉴定,为临床进行缺血性疾病的替代治疗奠定细胞学基础.方法 用灌注法分离小鼠骨髓血管内皮祖细胞,用血管内皮生长因子、成纤维细胞生长因子诱导其分化,形态学观察细胞的生长过程,并利用抗CD34抗体鉴定血管内皮祖细胞,利用抗vWF抗体、抗eNOS抗体鉴定血管内皮细胞. 结果小鼠骨髓血管内皮祖细胞可在体外培养条件下贴壁生长,可诱导分化为表达特异性组织蛋白的内皮细胞.结论 在小鼠骨髓内可分离出骨髓源性血管内皮祖细胞,呈贴壁增殖状态,并有分化能力.     

内皮型一氧化氮合酶在骨髓内皮祖细胞治疗缺血性脑血管病中的作用

内皮型一氧化氮合酶( eNOS)/NO在血管新生和血管发生中起着重要作用.脑缺血时,缺血组织内的eNOS表达增加,促进NO的释放,有利于骨髓内皮祖细胞(EPCs)的动员、迁移、归巢.而EPCs能在缺血组织分化为成熟的血管内皮细胞,修复损伤的内皮,参与新生血管的形成,改善组织细胞的供血.本文就eNOS在EPCs治疗缺血性脑血管病中的可能作用做一综述.     

基质细胞衍生因子-1及其受体CXCR4轴介导内皮祖细胞参与血管损伤修复的研究进展

<正>内皮祖细胞(endothelial progenitor cells,EPCs)能够参与血管损伤修复,给再生医学治疗带来了希望。Asahara等[1]从人类外周血中分离出内皮前体细胞,发现这种细胞参与缺血组织的血管新生。多项研究证实,EPCs通过分化成新生内皮细胞替代损伤的血管内皮,参与血管损伤修复[2-3]。EPCs参与血管损伤修复过程涉及EPCs动员、迁移、分化等一系列过程,期间多种因子通过多种途径参与调节此     

内皮祖细胞：缺血性卒中的潜在治疗靶点

内皮祖细胞(endothelial progenitor cells, EPCs)是一种未成熟的内皮细胞, 能够增殖并分化为成熟内皮细胞。EPCs在血管损伤后从骨髓迁移至缺血区域, 参与受损内皮修复和新生血管形成, 从而为治疗包括缺血性卒中在内的血管疾病提供了新的潜在治疗方法。文章就EPCs作为缺血性卒中潜在治疗靶点的可行性及局限性进行了综述。     

内皮祖细胞临床研究进展

内皮祖细胞（EPCs）是一种能分化为血管内皮细胞的前体细胞。目前发现成人体内存在EPCs，它可以从骨髓动员到外周血，分化为成熟的内皮细胞，并整合到血管损伤部位，参与血管修复。最近文献显示：循环EPCs的数量和功能可以作为内皮损伤的标志；在肢体缺血、心肌梗塞和中风治疗中具有重要作用。本文将对EPCs在临床研究中的应用作一综述。     

A role for planar cell polarity signaling in angiogenesis

The planar cell polarity (PCP) pathway is a highly conserved signaling cascade that coordinates both epithelial and axonal morphogenic movements during development. Angiogenesis also involves the growth and migration of polarized cells, although the mechanisms underlying their intercellular communication are poorly understood. Here, using cell culture assays, we demonstrate that inhibition of PCP signaling disrupts endothelial cell growth, polarity, and migration, all of which can be rescued through downstream activation of this pathway by expression of either Daam-1, Diversin or Inversin. Silencing of either Dvl2 or Prickle suppressed endothelial cell proliferation. Moreover, loss of p53 rescues endothelial cell growth arrest but not the migration inhibition caused by PCP disruption. In addition, we show that the zebrafish Wnt5 mutant (pipetail (ppt)), which has impaired PCP signaling, displays vascular developmental defects. These findings reveal a potential role for PCP signaling in the coordinated assembly of endothelial cells into vascular structures and have important implications for vascular remodeling in development and disease. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Estrogen induces endothelial progenitor cells proliferation and migration by estrogen receptors and PI3K-dependent pathways

Estrogen induces endothelial progenitor cells (EPCs) migration and proliferation, which may serve as a potential target for coronary artery disease, but the mechanisms are unclear. We hypothesized that estrogen receptors (ERs) and phosphatidylinositol 3-kinase (PI3K) signaling pathway, which represent particularly important roles of action for estrogen, may contribute to estrogen-induced EPCs migration and proliferation. Bone marrow mononuclear cells (MNCs) were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with growth factors as previously described. A total of 87.32+/-5.13% of adherent cells showed uptake of acetylated low-density lipoprotein and lectin binding. Immunostaining and fluorescence activated cell sorting confirmed the endothelial progenitor phenotype. RT-PCR, immunocytochemistry staining and Western blot demonstrated expression of ERs. Exposure to 17beta-estradiol significantly improved EPCs migration and proliferation. Those effects were blocked by pretreatment with the pharmacological PI3K blockers LY294002 (1 h, 10 micromol/L) and ICI-182780 (1 h, 10 micromol/L), a specific estrogen receptor antagonist, which show involvement of estrogen receptors and PI3K pathway. These results suggest that estrogen induces EPCs migration and proliferation via ERs and PI3K pathway which provided a novel insight and treatment strategy of vascular biology.     

Wnt信号通路在动脉粥样硬化及血管钙化中的研究进展

Wnt信号调控胚胎发育过程的多种生物学行为,包括细胞增殖、凋亡、细胞极性和器官发生,在胚胎发育过程起着重要作用。而在成人中,该信号处于沉默状态。最近证据表明,Wnt信号通路在许多生物学过程和疾病中被重新激活,参与代谢、炎症、肿瘤等疾病的发生,调节骨稳态,促进成骨细胞分化,诱导骨生成,并与动脉粥样硬化和血管钙化的发展进程密切相关。本文重点就Wnt信号通路的激活在内皮功能障碍、炎症反应、平滑肌细胞增殖及促进动脉粥样硬化和血管钙化等方面的作用进行综述。     

RhoA/ROCK信号通路与动脉粥样硬化关系的研究进展

动脉粥样硬化是一种常见的全身性血管疾病,同时也是多种急性心血管疾病的病理基础。而急性心血管疾病的死亡率高,严重危害人们的生命健康。近年来,越来越多的研究表明RhoA/ROCK信号通路与动脉粥样硬化的形成有密切联系。抑制RhoA/ROCK信号通路可以通过稳定血管内皮功能、抑制血管平滑肌细胞增殖和迁移、抑制血管钙化、调控炎症细胞聚集以及抑制血小板增殖变形来延缓或抑制动脉粥样硬化的形成。     

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...     

Involvement of progenitor cells in vascular repair

Whereas the genesis of an arterial lesion is thought to be the result of migration and proliferation of vascular cells, recent insights into the biology of progenitor cells now question this concept. Specifically, endothelial and smooth muscle cells appear to be derived from multiple sources such as circulating stem and progenitor cells, as well as tissue-resident progenitor cell populations. These cells may engraft at sites of vascular injury and play an integral role in vascular repair. In this review, experimental data from in vitro studies, animal models, and scattered human observations are reviewed in the context of emerging hypotheses regarding the response to vascular injury.     

Electroconvulsive seizure and VEGF increase the proliferation of neural stem-like cells in rat hippocampus

All classes of antidepressants increase hippocampal cell proliferation and neurogenesis, which contributes, in part, to the behavioral actions of these treatments. Among antidepressant treatments, electroconvulsive seizure (ECS) is the most robust stimulator of hippocampal cell proliferation and the most efficacious treatment for depression, but the cellular mechanisms underlying the actions of ECS are unknown. To address this question, we investigated the effect of ECS on proliferation of neural stem-like and/or progenitor cells in the subgranular zone of rat dentate gyrus. We define the neural differentiation cascade from stem-like cells to early neural progenitors (also referred to as quiescent and amplifying neural progenitors, respectively) by coexpression of selective cellular and mitotic activity markers. We find that at an early mitotic phase ECS increases the proliferation of quiescent progenitors and then at a later phase increases the proliferation of amplifying progenitors. We further demonstrate that vascular endothelial growth factor (VEGF) signaling is necessary for ECS induction of quiescent neural progenitor cell proliferation and is sufficient to produce this effect. These findings demonstrate that ECS and subsequent induction of VEGF stimulates the proliferation of neural stem-like cells and neural progenitor cells, thereby accounting for the superior neurogenic actions of ECS compared with chemical antidepressants.     

血管生成素1通过核因子κB传导通路调节内皮祖细胞炎症因子表达

目的探讨血管生成素1调节内皮祖细胞炎症因子的可能的信号传导通路。方法采用肿瘤坏死因子α诱导内皮祖细胞炎症,以慢病毒为载体将血管生成素1导入内皮祖细胞中,使用特异性抑制剂吡咯烷二硫代氨基甲酸盐抑制核因子κB,通过Western blot检测内皮祖细胞中血管生成素1蛋白和核因子κB蛋白的表达情况,随后采用荧光定量聚合酶链反应、酶联免疫吸附法检测各组内皮祖细胞中黏附分子细胞间黏附分子1、血管细胞黏附分子1的表达水平。结果转染血管生成素1基因内皮祖细胞中能够成功表达血管生成素1蛋白,而经吡咯烷二硫代氨基甲酸盐抑制后核因子κB蛋白未见明显表达。与肿瘤坏死因子α组相比,血管生成素1组、吡咯烷二硫代氨基甲酸盐组、血管生成素1+吡咯烷二硫代氨基甲酸盐组细胞间黏附分子1、血管细胞黏附分子1的mRNA和蛋白表达水平均明显下调(P<0.05),三组间无明显差异(P>0.05)。结论血管生成素1可能通过核因子κB信号传导通路影响肿瘤坏死因子α诱导的内皮祖细胞的炎症反应。     

Expression and secretion of vascular endothelial growth factor-A by cytokine-stimulated hematopoietic progenitor cells. Possible role in the hematopoietic microenvironment

In the hematopoietic microenvironment, bone marrow endothelial cells may play an important role in trafficking and maintenance of progenitor and stem cells due to adhesive interactions and paracrine secretion of hematopoietic growth factors. However, it is unknown whether progenitors in turn modulate endothelial proliferation and function.We analyzed mRNA expression (Northern blot) and release of vascular endothelial growth factor-A (VEGF-A), which specifically acts on endothelial cells, by cytokine-stimulated peripheral blood-derived CD34+ hematopoietic progenitor cells.While unstimulated CD34+ cells expressed VEGF-A mRNA weakly without cytokine release in vitro, incubation for 24 hours with a single cytokine (e.g., kit ligand [KL]) resulted in increased VEGF-A mRNA expression and significant secretion of VEGF-A into the supernatant. The amount of VEGF released was substantially augmented by incubation with a combination of cytokines (e.g., KL, IL-3, GM-CSF, G-CSF), or by exposure to hematopoietic cytokines for a longer time period. In addition, we show that VEGF induced the release of hematopoietic growth factors (GM-CSF) by bone marrow endothelial cells and that in vitro stromal cell-derived factor-1 (SDF-1) driven transendothelial progenitor cell migration was increased by the presence of VEGF, which might be due to pore formation (increased endothelial fenestration).In vivo, release of VEGF by progenitor cells may result in a paracrine loop supporting proliferation of both endothelium and progenitors and may facilitate transendothelial migration during cytokine-induced progenitor cell mobilization.