Angiostatin is an interesting inhibitor of angiogenesis with several reported molecular targets. The principal targets for its effect on endothelial and other cells needs to be clarified. Angiostatin and other angiogenesis inhibitors may have a variety of effects on normal vascular function both in modulating vascular anatomy and in producing transient effects on vasomotor tone.
Angiogenesis: The process of sprouting new capillaries from existing blood vessels. Although classically distinguished from vasculogenesis, the de novo formation of blood vessels during embryogenesis, recent studies have demonstrated overlap in these processes. Circulating endothelial progenitor cells may engraft in the vessel wall and contribute to neovascularization in the adult.
Angiostatin: An anti-angiogenic 38-kDa protein derived by proteolysis of plasminogen, consisting of the first 3 or 4 kringle domains.
Hepatocyte growth factor: An angiogenic growth factor also known as "scatter factor" that stimulates mitogenesis, motogenesis, and morphogenesis in cells that express its receptor, c-met.
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Thromb. Haemost. 87, 394-401. An excellent review of angiostatin with a focus on one of its first known cellular targets, ATP synthase. Moulton, K. S., Vakili, K., Zurakowski, D., Soliman, M., Butterfield, C., Sylvin, E., Lo, K.-M., Gillies, S., Javaherian, K., and Folkman, J. (2003). Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis. Proc. Natl. Acad. Sci. USA 100, 4736-4741. O'Reilly, M. S., Homgren, L. L., Shing, Y., Chen, C., Rosenthal, R. A., Moses, M., Lane, W. S., Cao, Y., Sage, E. H., and Folkman, J. (1994). Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79, 315-328. The original description of angiostatin with a particularly interesting discussion on the clinical observations suggesting that some primary tumors elaborate angiogenesis inhibitors. The discovery of a novel angiogenesis inhibitor derived from a known protein had major implications for the search for other novel bioactive protein derivatives and served as an excellent example for the value of proteomic-based solutions to diseases.
Rupnick, M. A., Panigraphy, D., Zhang, C.-Y., Dallabrida, S. M., Lowell, B. B., Langer, R., and Folkman, M. J. (2002). Adipose tissue mass can be regulated through the vasculature. Proc. Natl. Acad. Sci. USA 99, 10730-10735. This study demonstrates that obesity can be inhibited in mouse models by treatment with angiogenesis inhibitors including angiostatin. The study emphasizes the potential roles that angiogenesis inhibitors could have in a variety of diseases. Tarui, T., Miles, L. A., and Takada, Y. (2001). Specific interaction of angiostatin with integrin avß3 in endothelial cells. J. Biol. Chem. 276,
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Tuszynski, G. P., Sharma, M. R., Rothman, V. L., and Sharma, M. C. (2002). Angiostatin binds to tyrosine kinase substrate annexin II through the lysine-binding domain in endothelial cells. Microvasc. Res. 64, 448-462.
Wajih, N., and Sane, D. C. (2003). Angiostatin selectively inhibits signaling by hepatocyte growth factor in endothelial and smooth muscle cells. Blood 101, 1857-1863.
David C. Sane, M.D., is an Associate Professor of Internal Medicine in the Section of Cardiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina. Dr. Sane has studied structure-function relationships of the extracellular matrix protein vitronectin and its interaction with tranglutaminases. He is also interested in thrombosis and vascular biology and has examined the effect of angiostatin on HGF/C-met signaling.
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