EXTRACELLULAR MATRIX GUIDANCE OF CAPILLARY SPROUTING

众所周知，血管生成是许多 正常和病理情况，包括肌肉对运动的适应， 心肌对缺血、肿瘤发展和伤口愈合的适应。 通常情况下，新的血管是通过从已有的毛细血管或 微血管网络中的小静脉。已经证明，一种 缺乏血管内皮生长因子受体的周细胞样非内皮细胞引导毛细血管 从大鼠结缔组织中预先存在的微血管中发芽。这个周围虫 引导细胞在体内的微原纤维基质上迁移并产生第二个 临时基质可能是血管内皮细胞的支架 萌芽的近端部分。这项提议包括三个具体目标 旨在更好地阐明周细胞领导细胞， 微纤丝网络，以及周细胞产生的次生基质 引导细胞在毛细血管萌发中发挥作用。第一个具体目标是更好地 表征选定的细胞外基质蛋白的空间表达， 毛细血管芽中的整合素、生长因子和生长因子受体 肠系膜网络中的自发性及其周围组织区域 血管生成和血管生成对伤口愈合、炎症和 缺氧。第二个具体目标将利用体内的创新方法来 分析周细胞引导细胞和内皮细胞在血管内皮细胞上的迁移 对选定增长因素的应用作出反应的基础矩阵 (血管内皮生长因子、碱性成纤维细胞生长因子、血小板衍生生长因子-BB、转化生长因子β)。这里，对基质引导细胞的直接观察 体内将进行迁移或天然细胞外基质，从而 确定哪些生长因子能够作为化学引诱剂 在基质引导的毛细管萌发过程中。第三个具体目标是 研究中断选定的ECM-整合素相互作用的影响 关于毛细血管的组成和结构、微血管发育和 密度和网络图案。这个项目的长期目标是 了解类周细胞之间必须发生的分子相互作用 领导细胞、细胞外基质和内皮细胞产生 导致功能性微血管形成的毛细血管萌发 网络。通过更好地理解细胞和分子信号 在这个必不可少的过程中，我们也许最终能够找到 更好的介入抗血管生成治疗靶点，2找到更好的靶点 刺激缺血组织血管生成的靶点，以及3)组织 工程细胞外基质底物支持形成 体内有功能的微血管网络。

it is well known that angiogenesis is a critical component of many normal and pathological conditions, including muscle adaptation to exercise, myocardial adaptation to ischemia, tumor development, and wound healing. Typically, new blood vessels form by sprouting from pre-existing capillaries or small venules in the microvascular network. It has been shown that a periocyte-like, non-endothelial cell lacking VEGF receptors guides capillary sprouts from pre-existing microvessels in rat connective tissue. This pericytic guide cell migrates on a microfibril matrix in vivo and produces a second provisional matrix that may be a scaffolding for endothelial cells in the proximal portion of the sprout. This proposal consists of three specific aims that are designed to better elucidate the role that the pericytic leader cell, the microfibril network, and the secondary matrix produced by the pericytic guide cell play in capillary sprouting. The first specific aim is to better characterize the spatial expression of selected extracellular matrix proteins, integrins, growth factors, and growth factor receptors in the capillary sprout and surrounding tissue region in mesenteric networks undergoing spontaneous angiogenesis and angiogenesis in response to wound healing, inflammation, and hypoxia. The second specific aim will utilize an innovative in vivo approach to analyzing the migration of pericytic guide cells and endothelial cells on the underlying matrix in response to the application of selected growth factors (VEGF, bFGF, PDGF-BB, TGFbeta). Here, direct observations of matrix guided cell migration or native extracellular matrix will be made in vivo, thereby identifying which growth factors are capable of acting as chemoattractants during matrix guided capillary sprouting. 'The third specific aim is to investigate the impact that disrupting selected ECM-integrin interactions has on capillary sprout composition and structure, microvascular development and density and network patterning. The long term goal of this project is to understand the molecular interactions that must occur betweer the pericyte-like leader cells, the extracellular matrix, and the endothelial cells to produce capillary sprouting that leads to the formation of a functional microvascular network. By better understanding the cells and molecular signals that are essential for this essential process, we may eventually be able to, 1) find better targets for interventional anti-angiogenesis therapy, 2 find better targets for stimulating angiogenesis in ischemic tissues, and 3) tissue engineer extracellular matrix substrates the support the formation of functional microvascular networks in vivo.