Regulation of Endothelial Cell Function in Angiogenesis

血管生成是从预先存在的脉管系统增殖新血管。这是一个复杂的过程，需要内皮细胞从下面的基底膜解离，启动增殖程序，向刺激物迁移，然后退出细胞周期，更新与细胞外基质的附着，并重新建立形成功能性三维管状阵列的细胞间连接。该项目将重点关注内皮细胞的动态行为，其特征在于参与“血管生成开关”，并导致内皮细胞的动态行为，其特征在于参与“血管生成开关”，并导致形成稳定的血液流动管道。 我们计划四个紧密交错的项目，每个项目都涉及血管生成内皮细胞表型的一个新方面。项目1将研究内皮细胞以丝氨酸蛋白酶、纤溶酶的形式获得细胞表面蛋白水解的分子机制。新开发的annexin II null小鼠和annexin II promoter-LacZ转基因小鼠将被用来定义对annexin II的需求，以及其在几种血管生成中由动脉粥样硬化血栓形成氨基酸同型半胱氨酸（homocysteine）、血小板反应蛋白-1（thrombospondin-1）与其细胞表面受体CD 36相互作用并激活信号通路的调节。最近开发的CD 36裸小鼠将作为一种独特的试剂，用于检查该系统在血管生成。项目3将解决一个独特的G-蛋白偶联受体介导的CXC类趋化因子的血管生成作用的鉴定和表征。本计画将探讨该受体（一种假定的异源二聚体）及其配体和胞内信号蛋白的共刺激需求。项目4将考虑骨髓来源的内皮祖细胞的动员和募集及其在伤口愈合和其他新生血管反应期间参与血管生成。所有四个项目都将广泛利用三个支助设施。一个行政核心将为该方案提供预算、秘书和组织支助服务。组织技术核心将提供组织采购、处理和成像方面的技术专长和实际帮助。动物模型核心将提供一系列用于分析处理和成像的体内模型系统。动物模型核心将提供一系列用于分析小鼠血管生成的体内模型系统。总之，我们认为，该计划的项目和核心体现了一个动态的，互动的，富有成效的计划，与强大的机构支持，将成功地阐明新的机制和范式，启发我们的血管生成过程的理解。

Angiogenesis is the proliferation of new blood vessels from pre-existing vasculature. It is a complex process which requires that the endothelial cell dissociate from underlying basement membrane, initiate a proliferative program, migrate toward a stimulus, and then exit the cell cycle, renew attachment to extracellular matrix, and re-establish inter- cellular junctions forming a functional three-dimensional tubular array. This program project will focus on the dynamic behaviors of the endothelial cell which characterize its participation in the "angiogenic switch" and which lead dynamic behaviors of the endothelial cell which characterize its participation in the "angiogenic switch" and which lead to formation of a stable conduit for flowing blood. We plan four closely interdigitating projects each of which addresses a novel aspect of the angiogenic endothelial cell phenotype. Project 1 will examine the molecular mechanism by which the endothelial cell acquires cell surface proteolytic in the form of the serine protease, plasmin. Newly developed annexin II null mice and annexin II promoter-LacZ transgenic mice will be employed to define the requirement for annexin II, as well as its regulation by the atherothrombotic amino acid, homocysteine, in several angiogenesis, thrombospondin-1, interacts with its cell surface receptor CD36 and activates a signaling pathway. Recently developed CD36 null mice will serve as a unique reagent for examining this system in angiogenesis. Project 3 will address the identification and characterization of a unique G-protein coupled receptor that mediates the angiogenesis effects of the CXC class of chemokines. This project will investigate the co-stimulatory requirements of the receptor, a putative heterodimer, as well as its ligands and intracellular signaling proteins. Project 4 will consider the mobilization and recruitment of bone marrow- derived endothelial progenitor cells and their participation in angiogenesis during the wound healing and other neovascular responses. All four projects will make extensive use of three support facilities. An Administrative Core will provide budgetary, secretarial, and organization support services to the program. A Histotechnology Core will supply technical expertise and practical assistance with tissue procurement, processing, and imaging. An Animal Models Core will provide a series of in vivo model systems for the analysis of processing, and imaging. An Animals Models Core will provide a series of in vivo model systems for the analysis of angiogenesis in mice. In summary, we believe that the projects and cores of this program embody a dynamic, interactive, and productive program that, with strong institutional support, will succeed in elucidating new mechanisms and paradigms to enlighten our understanding of angiogenic processes.