Molecular basis of anti-angiogenic barriers in mesenchymal tissues

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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