Summary

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.

Glossary

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.

References

1. Benelli, R., Morini, M., Carrozzino, F., Ferrari, N., Minghelli, S., Santi, L., Cassatella, M., Noonan, D. M., and Albini, A. (2002). Neutrophils as a key cellular target for angiostatin: implications for regulation of angiogenesis and inflammation. FASEB J 16, 267-269.

2. Claesson-Welsh, L., Welsh, M., Ito, N., Anand-Apte, B., Soker, S., Zetter, B., O'Reilly, M., and Folkman, J. (1998). Angiostatin induces endothelial cell apoptosis and activation of focal adhesion kinase independently of the integrin-binding motif RGD. Proc. Natl. Acad. Sci. USA 95, 5579-5583.

3. Jiang, L., Jha, V., Dhanabal, M., Sukhatma, V. P., and Alper, S. I. (2001). Intracellular Ca2+ signaling in endothelial cells by the angiogenesis inhibitors endostatin and angiostatin. Am. J. Physiol. Cell Physiol. 280, C1140-C1150.

4. Gonzalez-Gronow, M., Kalfa, T., Johnson, C. E., Gawdi, G., and Pizzo, S. V. (2003). The voltage-dependent anion channel is a receptor for plasminogen kringle 5 on human endothelial cells. J. Biol. Chem. 278, 27312-27318.

5. Stack, M. S., Gately, S., Bafetti, L. M., Enghild, J. J., and Soff, G. A. (1999). Angiostatin inhibits endothelial and melanoma cellular invasion by blocking matrix-enhanced plasminogen activation. Biochem. J. 340, 77-84.

6. Mogford, J. E., Davis, G. E., Platts, S. H., and Meininger, G. A. (1996). Vascular smooth muscle alpha sub v beta sub 3 integrin mediates arteri-olar vasodilation in response to RGD peptides. Circ. Res. 79, 821-826.

7. Pascaud, M-A., Griscelli, F., Raoul, W., Marcos, E., Opolon, P., Raffestin, B., Perricaudet, M., Adnot, S., and Eddahibi, S. (2003). Lung overexpression of angiostatin aggravates pulmonary hypertension in chronically hypoxic mice. Am. J. Respir. Cell Miol. Biol. 29, 449-457.

Further Reading

Koshida, R., Ou, J., Matsunaga, T., Chilian, W. M., Oldham, K. T., Ackerman, A. W., and Pritchard, K. A., Jr. (2003). Angiostatin. A nega tive regulator of endothelial-dependent vasodilation. Circulation 107, 803-806. This study demonstrates a novel activity of angiostatin as a modulator of vascular tone. Angiostatin uncoupled eNOS from hsp90, decreasing NO production, while increasing O2". Matsunaga, T., Weihrauch, D. W., Moniz, M.C., Tessmer, J., Warltier, D. C., and Chilian, W. M. (2002). Angiostatin inhibits coronary angiogenesis during impaired production of nitric oxide. Circulation 105, 21852191.

Moser, T. L., Stack, M. S., Wahl, M., and Pizzo, S. V. (2002). The mechanism of action of angiostatin: Can you teach an old dog new tricks?

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,

39562-39568. v 3

Troyanovsky, B., Levchenko, T., Mänsson, G., Matvijenko, O., and Holmgren, L. (2001). Angiomotin: An angiostatin binding protein that regulates endothelial cell migration and tube formation. J. Cell. Biol. 152, 1247-1254.

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.

Capsule Biography

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.

Reducing Blood Pressure Naturally

Reducing Blood Pressure Naturally

Do You Suffer From High Blood Pressure? Do You Feel Like This Silent Killer Might Be Stalking You? Have you been diagnosed or pre-hypertension and hypertension? Then JOIN THE CROWD Nearly 1 in 3 adults in the United States suffer from High Blood Pressure and only 1 in 3 adults are actually aware that they have it.

Get My Free Ebook


Post a comment