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Molecular basis of anti-angiogenic barriers in mesenchymal tissues

间充质组织抗血管生成屏障的分子基础

基本信息

批准号：
17014046
负责人：
HIRAKI Yuji
金额：
$ 29.06万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2009
项目状态：
已结题

项目摘要

In general, mesenchymal tissues are well-vascularized and permissive to vascular invasion upon stimulation by proangiogenic stimuli. However, anti-angiogenic mesenchymes are also known in the body. Abnormal vascular invasion into these tissues is devastating to physiological functions in organs and often pathogenic. In this study, we investigate the molecular basis of anti-angiogenic properties of mesenchymal structures with special attention to tissue-specific angiogenesis inhibitors, chondromodulin-I (ChM-I) and tenomodulin (Tnmd). Our present results indicate that the angiogenic signal balance between VEGF-A vs. ChM-I/Tnmd underlies the control of tissue vascularity and vascular homeostasis. Moreover, we clearly demonstrated that the loss of these inhibitors plays an important pathogenic role in angiogenic diseases as well as the overexpression of angiogenic factors such as VEGF-A. In the meantime, we successfully expressed recombinant human ChM-I with a high specific activity compa … More rable to that of naturally occurring ChM-I. Using this preparation of recombinant protein, we have shown that ChM-I inhibits angiogenic actions of cultured vascular endothelial cells in response to VEGF-A through a unique mode of signaling pathway. Then, to gain a further insight into functions of anti-angiogenic barriers, we attempted to visualize anti-angiogenic barriers during endochondral bone formation by overexpressing VEGF-A with a viral vector in chick limb buds. Circulating microvessels were visualized by injecting India ink through the extraembryonic vitelline vein. VEGF-A thus expressed dramatically induced a high density of vasculature in connective tissue, which enabled us to identify perichondrial anti-angiogenic barriers surrounding cartilaginous bone rudiments for the first time. This novel anti-angiogenic barrier is regulated by a specific mode of VEGF-A signal reception and plays a central role in vascular invasion into cartilage to occur. These results will provide a important clue to the development of a novel anti-tumor therapy. Less

一般来说，间充质组织血管化良好，在促血管生成刺激物的刺激下允许血管侵入。然而，体内也存在抗血管生成间充质。对这些组织的异常血管侵入对器官的生理功能具有破坏性，并且通常是致病的。在本研究中，我们研究了间充质结构抗血管生成特性的分子基础，特别关注组织特异性血管生成抑制剂、软骨调节素-I (ChM-I) 和腱调节素 (Tnmd)。我们目前的结果表明，VEGF-A 与 ChM-I/Tnmd 之间的血管生成信号平衡是组织血管分布和血管稳态控制的基础。此外，我们清楚地证明，这些抑制剂的缺失在血管生成疾病以及血管生成因子（如 VEGF-A）的过度表达中起着重要的致病作用。同时，我们成功表达了重组人 ChM-I，其比天然 ChM-I 具有更高的比活性。使用这种重组蛋白制剂，我们发现 ChM-I 通过独特的信号通路模式抑制培养的血管内皮细胞响应 VEGF-A 的血管生成作用。然后，为了进一步了解抗血管生成屏障的功能，我们尝试通过在鸡肢芽中用病毒载体过度表达 VEGF-A 来可视化软骨内骨形成过程中的抗血管生成屏障。通过胚胎外卵黄静脉注射印度墨水来观察循环微血管。因此，VEGF-A 的表达显着诱导结缔组织中脉管系统的高密度，这使我们能够首次识别软骨骨雏形周围的软骨周抗血管生成屏障。这种新型抗血管生成屏障由 VEGF-A 信号接收的特定模式调节，并在血管侵入软骨的发生中发挥核心作用。这些结果将为开发新型抗肿瘤疗法提供重要线索。较少的