Molecular basis of anti-angiogenic barriers in mesenchymal tissues

一般来说，间充质组织血管化良好，并且在受促血管生成刺激物刺激时允许血管侵入。然而，抗血管生成间充质也是已知的。异常血管侵入这些组织对器官的生理功能是毁灭性的，并且通常是致病的。在这项研究中，我们研究了间充质结构的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）。我们目前的研究结果表明，VEGF-A与ChM-I/Tnmd之间的血管生成信号平衡是控制组织血管和血管稳态的基础。此外，我们清楚地表明，这些抑制剂的损失在血管生成疾病以及血管生成因子如VEGF-A的过表达中起着重要的致病作用。同时，我们成功地表达了具有高比活性的重组人ChM-Ⅰ，并在大肠杆菌中进行了表达。 ...更多信息 与天然存在的ChM-I相似。使用这种重组蛋白的制备，我们已经表明，ChM-I抑制血管生成的行动，培养的血管内皮细胞响应VEGF-A通过一个独特的模式的信号传导途径。然后，为了进一步了解抗血管生成屏障的功能，我们试图通过在鸡肢芽中过表达VEGF-A与病毒载体来可视化软骨内骨形成期间的抗血管生成屏障。通过胚外卵黄静脉注射印度墨水观察循环微血管。因此，VEGF-A的表达显着诱导结缔组织中的高密度血管，这使我们能够确定周围的软骨骨雏形的软骨膜抗血管生成障碍的第一次。这种新的抗血管生成屏障由VEGF-A信号接收的特定模式调节，并在血管侵入软骨中发挥核心作用。这些结果将为开发新的抗肿瘤治疗方法提供重要线索。少

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