题目：Molecular analysis of blood vessel maturation

报告人：Nobuyuki Takakura

Professor of Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

主持人：韩晶岩 （中西医结合教研室，微循环研究中心）

时间：2007年11月8日（周4）16：00-17：00

地点：基础医学院生化楼3楼会议室

 

摘要：Blood vessels play a fundamental role in supplying cells with oxygen. The vascular system of vertebrates has a highly organized hierarchical structure, ranging from large blood vessels down to finely sized capillaries. This closed circular system enables vital fluids to be transported rapidly around the body to reach whole organs and tissues. The intra-luminal cavity of blood vessels is lined almost exclusively with endothelial cells (ECs). The formation of blood vessels is initiated by the assembly and tube formation of ECs, or EC progenitors. This process is termed vasculogenesis and is followed by angiogenesis, which results in the emergence of new vessels through the sprouting and elongation from, or the remodeling of, preexisting vesselsDuring the process of angiogenesis, ECs have to decide the direction of migration and inhibit vascular leakage even in the absence of mural cell (MC) adhesion to ECs. In these processes, we found that hematopoietic stem cells (HSCs) play a role in promoting migration of ECs as a guidepost through angiopoietin-1 (Ang1) production and we determined that Ang1 from HSCs inhibits permeability of newly branching blood vessels through inhibition of ACE transcription. Moreover, such HSCs have a potential to differentiate into MCs for the mechanical stabilization of newly developed blood vessels.    

  In the final step of angiogenesis, blood vessels change their caliber to adapt to the demands of tissues or organs for oxygen and nutrients. However, the molecular regulatory mechanism of caliber size modification in blood vessels is not clear. We found that HSCs surrounding newly developed vessels induce caliber change of blood vessels into larger one. This effect was observed in fibrous cap of tumor. We found that apelin, a protein secreted from ECs under the activation of Tie2 receptor tyrosine kinase on ECs, plays a role in the decision of caliber size of blood vessel through its cognate receptor APJ, expressed on ECs. Apelin induced enlarged capillaries in tumors and cornea, and apelin?deficient mice showed narrow blood vessels in intersomitic vessels during embryogenesis and in the trachea and dermis in the adult. Apelin induced EC proliferation in the presence of VEGF and promoted cell-to-cell aggregation by regulating adhesion molecules. These results indicated that the apelin/APJ system is involved in size?sensing mechanism of blood vessels during angiogenesis.      

Main publication:

1.       Yamada Y. Takakura N.: Physiological pathway of differentiation of hematopoietic stem cell population into mural cells. J Exp Med. 203:1055-1065, 2006

2.       Takakura N., Watanabe T., Suenobu S., Yamada Y., Noda T., Ito Y., Satake M. & Suda T. : A role for hematopoietic stem　cells in promoting angiogenesis. Cell 102:199-209 2000

3.       Takakura N., Huang X.L., Naruse T., Hamaguchi I., Dumont D.J., Yancopoulos G.D. &  Suda T. :Critical role of the TIE2  endothelial cell receptor in the development of definitive hematopoiesis. Immunity 9:677-686 1998

4.       Takakura N., Kodama H., Nishikawa S. & Nishikawa S. :Preferential proliferation of murine colony-forming units in culture in a chemically defined condition with a macrophage colony-stimulating factor-negative stromal cell clone.  J. Exp. Med. 184: 2301-2309 1996