胚胎发育中血管新生的研究

在胚胎发育中,心血管系统最早发育并发挥运输氧和营养物质的功能。在原肠运动时期,中胚层细胞在相邻内胚层细胞信号的诱导下分化产生内皮细胞,从而开始形成血管系统。血管新生是形成完整血管系统的重要过程,主要包括出芽式血管新生和套叠式血管新生两种方式。出芽式血管新生最为普遍,主要包括基底膜的降解、内皮细胞的迁移和增殖、管腔形成和血管的成熟与稳定四步。由于血管新生对胚胎发育以及许多生理过程均发挥重要作用,血管新生受到多条信号通路的精密调控。该文从内皮细胞的来源、血管新生的过程及信号调控三个方面就近年来胚胎发育中血管新生的研究作简要综述。     

自噬与血管新生相关细胞因子

血管新生发生于机体多种生理病理过程中,已成为诸多病理过程的标志之一。自噬参与调节机体血管新生。在病变组织中,自噬不仅与血管形成密切相关,而且经调节血管新生向病理组织提供必要的氧与能量。通过抑制自噬可以抑制缺氧、能量缺乏等刺激诱导的血管新生。血管新生过程中相关细胞因子参与调节自噬而影响新生血管的形成。通过二者的作用,既可以促进血管新生,也可抑制血管新生,这种机制在机体生理和病理过程中具有重要的作用。本文从自噬通过血管新生细胞因子促进血管新生以及自噬通过血管新生细胞因子抑制血管新生两个方面概述了自噬在血管新生过程中的作用,为疾病的治疗提供新的思路与方法。     

Hedgehog信号通路靶基因与肿瘤的关系之研究进展

Hedgehog（HH）蛋白属于分泌蛋白家族,广泛表达于哺乳动物,非哺乳动物等多个物种,参与调控多种肿瘤形成,器官成熟、血管生成,干细胞分化,免疫细胞以及胚胎发育。文章主要就近几年来国内外对hedgehog信号通道下游靶基因在肿瘤干细胞,肿瘤细胞的转移,增殖,凋亡及胚胎发育等方面的研究进展进行综述,重点阐述hedgehog信号通路下游靶基因与肿瘤及发育的关系,以期能为与hedgehog信号通道参与调控的相关疾病提供一些靶向性临床诊疗的新思路。     

Nogo-B受体的生物学功能

Nogo-B受体(Nogo-B receptor, NgBR)是网状蛋白家族4成员Nogo-B的受体,广泛分布于机体的多种组织和器官,并定位于细胞膜及内质网。NgBR参与了体内多种生理和病理生理过程,如多萜醇合成、脂肪代谢、胆固醇转运,以及胰岛素抵抗、血管重塑和生成、肿瘤形成和神经系统疾病等。本文拟对近年来关于NgBR的结构与功能做一简要综述。对NgBR的结构及功能的进一步探究,将有助于深入了解其参与各种疾病的作用机制,为疾病的防治提供可能的临床策略。     

Hedgehog信号通路在胚胎发育过程中的调控作用

Hedgehog信号通路首次在果蝇体内被发现,进化上呈高度保守状态。该通路在胚胎发育、机体组织器官的形成过程中发挥了重要作用,它的异常调节会导致一系列严重的疾病。本文主要就Hedgehog信号通路对神经系统、骨骼系统、消化系统、肺、颅面部发育的调控作用作一综述。     

血管管腔形成的遗传调控

血管系统是脊椎动物机体中最早发育并行使重要生理功能的复杂系统。血管管腔形成启始于心脏开始跳动和所有其他组织器官形成之前,对于促进血管系统的精确建成和有效灌流,通过营养运输、气体交换和代谢废物清除以确保所有组织器官的形成和生长至关重要。在血管发育过程的两个阶段,即血管发生(vasculogenesis)和血管形成(angiogenesis)中,有效管腔的形成和维持均是保证血管正常发育并行使生理功能的关键环节。血管管腔形成大致可以分为两个关键环节:血管管腔形成的诱导以及内皮细胞极性的建立和维持。重点依据体内遗传修饰模式生物方面的研究结果,从上述两个环节分别阐述血管管腔形成的遗传调控机制。     

斑马鱼管腔器官空腔形态发生及分子机制

后生动物复杂的体内结构和器官结构多以网络状的管道系统出现。中空的管腔作为这个系统的重要结构单元承担了运输物质、区分器官不同部位功能、分隔机体和外环境等诸多重要的生理功能。管腔的发育障碍将致使相关器官形态发生畸形、功能紊乱。管腔型器官形态发生易被直接观察以及各种相关突变鱼和荧光转基因鱼的出现, 使得斑马鱼(Danio rerio)成为管道器官研究的优秀模式动物。斑马鱼血管、神经管、小肠、胰腺外分泌腺、前肾管等几种重要的器官的形态发生都伴随着典型的腔道发育过程, 是研究管腔形成的重要器官模型。管腔形成由胞外信号诱导、细胞极性化、胞内物质定向运输、腔内液体形成和胞内细胞骨架重构等相关管腔细胞内外发生的结构功能变化过程所构成, 而这些结构与功能的变化过程是通过精确而复杂的分子调控网络来实现, 最终形成管道器官。文章对斑马鱼4种典型管腔型器官的空腔形态发生过程进行了综述, 并总结了此过程中的分子机制, 为今后的相关研究提供了参考。     

Wnt信号通路与皮肤创面愈合的关系

创面愈合是由炎性细胞、细胞因子等多种因素共同参与,涉及组织修复、再生、重建的一个复杂有序的病理生理过程。皮肤慢性创面的愈合仍然是临床研究的重点与热点,随着分子生物学的发展,对皮肤创面愈合机制的认识也逐渐深入。Wnt信号通路是一条由Wnt蛋白及其受体、调节蛋白等组成的高度保守的信号通路,参与细胞增殖、凋亡、分化等多种生物学过程。Wnt信号通路作为参与皮肤愈合的信号通路之一,被认为具有调控皮肤及其附属器的发育、诱导皮肤附件的形态发生、调节毛囊的周期生长、促进创面血管新生及上皮重塑等多方面的功能。因此本文试从炎性细胞、成纤维细胞、干细胞、血管新生、表皮新生与毛囊新生等方面对Wnt信号通路与皮肤创面愈合的关系作一综述。     

缺氧诱导因子-1结构及功能的研究进展

缺氧诱导因子(hypoxia inducible factor-1,HIF-1)是一种介导机体对缺氧环境产生应答的转录因子。在炎症及实体肿瘤周围的组织大多存在缺氧现象。在缺氧条件下,HIF-1α和HIF-1β两个亚基结合,形成HIF-1并迅速活化,参与机体缺氧环境的适应,并在胚胎发育、多种肿瘤及心肺疾病等发生发展中起到重要作用。因此,更好地认识HIF-1的功能及意义,对进一步地认识与其相关生命过程和疾病本质以及研发新的治疗手段具有重要意义。     

缺氧如何诱导果蝇气管发生分枝

昆虫体内的循环系统一般不参与氧气运输,各组织和器官所需的氧气直接由气管系统供应。与哺乳动物的血管生成过程相似,昆虫气管的末端也能够产生分枝并侵入缺氧组织内。以往研究表明,果蝇体内处于缺氧状态的细胞会产生Bnl,这是成纤维细胞生长因子的同源体,其受体Btl位于气管细胞     

Implantation of Fibrin Gel on Mouse Lung to Study Lung-specific Angiogenesis

Recent significant advances in stem cell research and bioengineering techniques have made great progress in utilizing biomaterials to regenerate and repair damage in simple tissues in the orthopedic and periodontal fields. However, attempts to regenerate the structures and functions of more complex three-dimensional (3D) organs such as lungs have not been very successful because the biological processes of organ regeneration have not been well explored. It is becoming clear that angiogenesis, the formation of new blood vessels, plays key roles in organ regeneration. Newly formed vasculatures not only deliver oxygen, nutrients and various cell components that are required for organ regeneration but also provide instructive signals to the regenerating local tissues. Therefore, to successfully regenerate lungs in an adult, it is necessary to recapitulate the lung-specific microenvironments in which angiogenesis drives regeneration of local lung tissues. Although conventional in vivo angiogenesis assays, such as subcutaneous implantation of extracellular matrix (ECM)-rich hydrogels (e.g., fibrin or collagen gels or Matrigel - ECM protein mixture secreted by Engelbreth-Holm-Swarm mouse sarcoma cells), are extensively utilized to explore the general mechanisms of angiogenesis, lung-specific angiogenesis has not been well characterized because methods for orthotopic implantation of biomaterials in the lung have not been well established. The goal of this protocol is to introduce a unique method to implant fibrin gel on the lung surface of living adult mouse, allowing for the successful recapitulation of host lung-derived angiogenesis inside the gel. This approach enables researchers to explore the mechanisms by which the lung-specific microenvironment controls angiogenesis and alveolar regeneration in both normal and pathological conditions. Since implanted biomaterials release and supply physical and chemical signals to adjacent lung tissues, implantation of these biomaterials on diseased lung can potentially normalize the adjacent diseased tissues, enabling researchers to develop new therapeutic approaches for various types of lung diseases.     

Angiogenesis and organ transplantation

Angiogenesis is a vessel development process that maintains the vascular supply for organ function. Regulation of angiogenesis is provided by positive factors, such as vascular endothelial or basic fibroblast growth factors, and negative factors, such as thrombospondin and macrophage-derived inflammatory cytokines. While the role of angiogenesis in the wound healing, embryogenesis, tumor growth and proliferative diseases is clear, in organ transplantation it is not yet well established. Herein we discuss the potential role of angiogenesis in chronic renal disease and in transplant settings.     

Whole Mount Immunofluorescent Staining of the Neonatal Mouse Retina to Investigate Angiogenesis In vivo

Angiogenesis is the complex process of new blood vessel formation defined by the sprouting of new blood vessels from a pre-existing vessel network. Angiogenesis plays a key role not only in normal development of organs and tissues, but also in many diseases in which blood vessel formation is dysregulated, such as cancer, blindness and ischemic diseases. In adult life, blood vessels are generally quiescent so angiogenesis is an important target for novel drug development to try and regulate new vessel formation specifically in disease. In order to better understand angiogenesis and to develop appropriate strategies to regulate it, models are required that accurately reflect the different biological steps that are involved. The mouse neonatal retina provides an excellent model of angiogenesis because arteries, veins and capillaries develop to form a vascular plexus during the first week after birth. This model also has the advantage of having a two-dimensional (2D) structure making analysis straightforward compared with the complex 3D anatomy of other vascular networks. By analyzing the retinal vascular plexus at different times after birth, it is possible to observe the various stages of angiogenesis under the microscope. This article demonstrates a straightforward procedure for analyzing the vasculature of a mouse retina using fluorescent staining with isolectin and vascular specific antibodies.     

眼睛发育与骨形成蛋白信号通路的关系

在早期胚胎发育过程中,眼睛是由起源于不同胚层的几个部分经过一系列的诱导作用以及时间和空间上的相互协调作用形成的复杂而又具有精确功能的器官。在眼睛的形成发育过程中,许多信号通路及其相关的调控因子发挥着重要作用。本文主要关注眼睛发育过程与骨形成蛋白(BMP)信号通路的关系,BMP信号的激活能够诱导晶状体的再生和CLT(角膜到晶状体的分化转移)进程,维持睫状体的功能,促进视网膜的发生,影响巩膜的重塑和泪腺的发育。很多眼部疾病的发生与BMP信号通路的调节紊乱密切相关,因此可以将BMP信号通路作为一个潜在的药物靶点来探究治疗眼部疾病的方法。本文就BMP信号通路对眼睛发育的影响作一综述。     

Ang-Tie轴在血管和淋巴系统相关疾病中作用的研究进展

形成血管和淋巴管内层的内皮细胞是脉管系统的重要组成部分,并参与血管和淋巴系统疾病的发病机制。内皮细胞上的血管生成素(Angiopoietin,Ang)-具有免疫球蛋白和表皮生长因子同源性结构域的酪氨酸蛋白激酶(Tyrosine kinase receptors with immunoglobulin and EGF homology domains,Tie)轴是除了血管内皮生长因子受体途径外胚胎心血管和淋巴发育所必需的第二种内皮细胞特异性配体-受体信号传导系统。Ang-Tie轴参与调节产后血管生成与重塑、血管通透性和炎症,以维持血管平衡,因此,该系统在许多血管和淋巴系统疾病中发挥重要的作用。针对近年来Ang-Tie轴在血管和淋巴系统相关疾病中作用的研究进展,文中系统论述了Ang-Tie轴在炎症诱导的血管通透性、血管重塑、眼部新生脉管、剪切应力反应、动脉粥样硬化和肿瘤血管生成和转移中的作用,并总结了涉及Ang-Tie轴的相关治疗性抗体、重组蛋白和小分子药物。     

解偶联蛋白2在内皮损伤及血管重构中的作用研究进展

心脑血管疾病是全球最主要的致死性疾病。活性氧(Reactive oxygen species,ROS)产生增多诱发血管内皮细胞损伤、平滑肌细胞迁移、增殖,是导致血管功能障碍、血管重构发生的重要机制。因此,氧化应激被认为是心脑血管疾病发生、发展的关键环节。但通过补充外源性抗氧化剂防治心脑血管疾病一直存在较大争议。机体可通过自身防御体系拮抗氧化应激,维持氧化-还原状态,如通过调控线粒体解偶联蛋白2(Uncoupling protein 2,UCP2)调节ROS生成,改善血管功能障碍及血管重构。本文就UCP2在内皮损伤及血管重构中的作用及机制展开综述,为深入探索这一潜在的防治心脑血管疾病的靶点提供信息。     

On the Mechanics of Cardiac Function of Drosophila Embryo

The heart is a vital organ that provides essential circulation throughout the body. Malfunction of cardiac pumping, thus, leads to serious and most of the times, to fatal diseases. Mechanics of cardiac pumping is a complex process, and many experimental and theoretical approaches have been undertaken to understand this process. We have taken advantage of the simplicity of the embryonic heart of an invertebrate, Drosophila melanogaster, to understand the fundamental mechanics of the beating heart. We applied a live imaging technique to the beating embryonic heart combined with analytical imaging tools to study the dynamic mechanics of the pumping. Furthermore, we have identified one mutant line that exhibits aberrant pumping mechanics. The Drosophila embryonic heart consists of only 104 cardiac cells forming a simple straight tube that can be easily accessed for real-time imaging. Therefore, combined with the wealth of available genetic tools, the embryonic Drosophila heart may serve as a powerful model system for studies of human heart diseases, such as arrhythmia and congenital heart diseases. We, furthermore, believe our mechanistic data provides important information that is useful for our further understanding of the design of biological structure and function and for engineering the pumps for medical uses.     

Notoginsenoside R1 activates the Ang2/Tie2 pathway to promote angiogenesis

BackgroundTherapeutic angiogenesis is a novel strategy for the treatment of ischemic diseases that involves promotion of angiogenesis in ischemic tissues via the use of proangiogenic agents. However, effective proangiogenic drugs that activate the Ang2/Tie2 signaling pathway remain scarce.PurposeWe aimed to investigate the proangiogenic activity of notoginsenoside R1 (NR1) isolated from total saponins of Panax notoginseng with regard to activation of the Ang2/Tie2 signaling pathway.MethodsWe examined the proangiogenic effects of NR1 by assessing the effects of NR1 on the proliferation, migration, invasion and tube formation of human umbilical vein endothelial cells (HUVECs). The aortic ring assay and vascular endothelial growth factor receptor inhibitor (VRI)-induced vascular regression in the zebrafish model were used to confirm the proangiogenic effects of NR1 ex vivo and in vivo. Furthermore, the molecular mechanism was investigated by Western blot analysis.ResultsWe found that NR1 promoted the proliferation, mobility and tube formation of HUVECs in vitro. NR1 also increased the number of sprouting vessels in rat aortic rings and rescued VRI-induced vascular regression in zebrafish. NR1-induced angiogenesis was dependent on Tie2 receptor activation mediated by increased autocrine Ang2 in HUVECs, and inhibition of the Ang2/Tie2 pathway abrogated the proangiogenic effects of NR1.ConclusionsOur results suggest that NR1 promotes angiogenesis by activating the Ang2/Tie2 signaling pathway. Thus, NR1-induced activation of the Ang2/Tie2 pathway is an effective proangiogenic approach. NR1 may be useful agent for the treatment of ischemic diseases.     

NAD/NADP及其介导氧化应激在神经退行性疾病中的作用

神经退行性疾病如阿尔茨海默病、帕金森病、亨廷顿病等疾病的发生与氧化应激紧密相关。NAD和NADP是维持氧化系统和抗氧化系统平衡的两个关键物质。NAD和NADP的生物合成和降解有多种途径,参与其生物途径的物质如NAMPT、NADK、PARP1、SIRT1、CD38等,均报道在神经退行性疾病发挥一定的作用。因此,本文分别从NAD和NADP的合成和降解途径中的一些关键物质出发,结合氧化应激总结并探讨它们在神经退行性疾病的作用,以期为临床治疗神经退行性疾病提供新思路。