Adult Tissue Morphogenesis: Functional Regulation of Intussusceptive Angiogenesis

成人组织形态发生：套叠血管生成的功能调节

• 批准号: 8843029
• 负责人: STEVEN MENTZER
• 金额: $ 38.21万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-22 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8843029
• 关键词: 3-Dimensional; Address; Adult; Alveolar; Blood; Blood Circulation; Blood Vessels; Blood capillaries; Blood flow; Bone Marrow; Cells; Colitis; Colon; Computer Simulation; Corrosion Casting; Cross Circulation; Deposition; Dermatitis; Development; Developmental Process; Embryonic Development; Endothelial Cells; Fluorescence; Frequencies; Goals; Growth; Health; Image; Island; Lung; Modeling; Morphogenesis; Mouse Protein; Natural regeneration; Physiological Processes; Pneumonectomy; Process; Proteins; Regenerative Medicine; Regulation; Scanning Electron Microscopy; Shapes; Skin; Staging; Stem cells; Stretching; Testing; Therapeutic; Tissue Engineering; Tissues; Wild Type Mouse; angiogenesis; capillary; density; hemodynamics; human tissue; in vitro Model; interdisciplinary approach; mature animal; migration; morphometry; mouse model; neovascularization; peripheral blood; therapeutic angiogenesis; tissue repair

DESCRIPTION (provided by applicant): A biologic process that rapidly expands vascular networks is intussusceptive (nonsprouting) angiogenesis. Vascular expansion occurs by the active subdivision of one vessel into two lumens. The earliest stage of this process is characterized by the formation of tissue islands or intraluminal "pillars." We have found these intravascular pillars in the skin (dermatitis), colon (colitis) and lung (post-pneumonectomy). Growth or extension of the intraluminal pillars down the axis of the vessel leads to vessel duplication. The rate of pillar extension and vascular division appears to far exceed the proliferative capacity of resident endothelial cells. This project addresses the following question How is the process of adult intussusceptive angiogenesis capable of such rapid blood vessel expansion; further, how can this process be harnessed for therapeutic angiogenesis? To answer this question, we have developed a parabiotic mouse model of post-pneumonectomy intussusceptive angiogenesis. In the parabiotic model, wild-type and green fluorescence protein (GFP) mice are surgically paired to establish complete cross-circulation. After establishing a shared circulation, a pneumonectomy is performed in the wild-type mouse. Morphometry demonstrates that the remaining lung develops 1-3 kilometers of new alveolar capillaries within 2 weeks of pneumonectomy. Corrosion casting and 3-dimensional scanning electron microscopy shows that this blood vessel growth is largely produced by intense intussusceptive angiogenesis. An important clue to understanding the process of intussusceptive angiogenesis is the observation that post-pneumonectomy vessel growth is associated with GFP+ endothelial cells. Since the intussusceptive angiogenesis occurs in the wild-type mouse, GFP+ cells in the vascular lining must be derived from the peripheral blood circulation. These GFP+ endothelial progenitor cells (EPC) not only demonstrate the importance of EPC in intussusceptive angiogenesis, but they provide an explanation for the rapid rate of vascular expansion. Adding further support for the importance of EPC, we have demonstrated that, in studies of parabiotic colitis, blood-borne EPC localize near intussusceptive pillars. To test our hypothesis that intussusceptive pillars localize circulating EPC, we will use the parabiotic model to track endothelial progenitor cells (EPC) from their mobilization in the bone marrow to their migration into the lung during parabiotic post-pneumonectomy intussusceptive angiogenesis (Specific Aim #1). Advanced imaging will determine the effect of intussusceptive pillars on EPC localization, vascular integration and total angiogenesis (Specific Aim #2). Finally, the intravascular interaction of EPC and pillars during intussusceptive angiogenesis will be modeled in vitro and in silico (Specific Aim #3). The goal of this project is the functional regulation of adult intussusceptive angiogenesis; that is, the rapid expansion of microvascular networks for application in both regenerative medicine and tissue engineering.

描述（由申请人提供）：一种快速扩展血管网络的生物学过程是肠use useptective（非刺）的血管生成。血管膨胀是通过将一个容器的主动细分分成两个流明而发生的。该过程的最早阶段的特征是形成组织岛或腔内“支柱”。我们发现皮肤（皮炎），结肠炎（结肠炎）和肺（肺切除术）中的这些血管内支柱。沿血管轴的腔内支柱的生长或延伸导致血管复制。支柱延伸和血管分裂的速率似乎远远超过了居民内皮细胞的增殖能力。该项目解决了以下问题，成人肠胃血管生成的过程如何能够这种快速血管扩张？此外，该过程如何用于治疗性血管生成？为了回答这个问题，我们已经开发了一种对肠内切除术后血管生成的副生物小鼠模型。在对抗生素模型中，野生型和绿色荧光蛋白（GFP）小鼠进行手术配对以建立完整的交叉循环。建立共同的循环后，在野生型小鼠中进行了肺切除术。形态计量学表明，其余的肺在肺炎切除术后2周内形成1-3公里的新牙槽毛细血管。腐蚀铸造和三维扫描电子显微镜表明，这种血管的生长在很大程度上是由强烈的肠tussuseptive性血管生成产生的。理解肠胃痛的血管生成过程的一个重要线索是，观察到肺切除术后血管生长与GFP+内皮细胞有关。由于肠内血管生成发生在野生型小鼠中，因此血管内膜中的GFP+细胞必须源自外周血循环。这些GFP+内皮祖细胞（EPC）不仅证明了EPC在肠内血管生成中的重要性，而且还为血管扩张速度快速率提供了解释。为EPC的重要性增加了支持，我们已经证明，在对pro鼻结肠炎的研究中，血源性EPC定位于肠use依柱附近。为了检验我们的假设，即肠胃us鼻柱将循环的EPC定位，我们将使用抛害生成模型从骨髓中的动员到par养生后的骨髓术后迁移到肺部肠道切除术后肠道切除术后肠道肠道切除术肠道肠道肠道静脉us静性静脉复合物（特定的AIM＃1）。先进的成像将确定肠use子术支柱对EPC定位，血管整合和总血管生成的影响（特定目标＃2）。最后，将在体外和计算机中对EPC和支柱的血管内相互作用进行建模（特定目标＃3）。该项目的目的是对成人肠胃血管生成的功能调节。也就是说，在再生医学和组织工程中应用微血管网络的快速扩展。