Regulatory Aspects of Neovascularization

Regulation of Wound Angiogenesis by Metabolic Alterations
  • M. Zamirul Hussain
  • Q. Perveen Ghani
  • John J. Feng
  • Thomas K. Hunt
Part of the Cancer Drug Discovery and Development book series (CDD&D)


Angiogenesis is a critical component of tissue repair and involves a series of interconnected, interdependent events, among which are generation and reception of angiogenic signals, chemotaxis, proteolysis of extracellular matrix, cell replication, cell-matrix adhesion, tube formation, and ligation of the newly formed vascular sprouts. The discovery of angiogenic cytokines and growth factors has greatly contributed to understanding ofthe regulation of angiogenesis (1–3). Although many angiogenic substances have been found that potentially upregulate most of the above mentioned angiogenic events, no unifying postulate for their synthesis or their mode of action has emerged. Perhaps a search for how these substances are elicited may prove to be a fruitful alternative. Only recently have research efforts touched on how the initiation of angiogenesis could be linked to the metabolic state (4).


Vascular Endothelial Growth Factor Angiogenic Activity Vascular Endothelial Growth Factor Gene Prolyl Hydroxylase Vascular Endothelial Growth Factor Release 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Folkman, J. and Shing, Y. (1992) Angiogenesis. J. Biol. Chem. 267, 10,931–10,934.Google Scholar
  2. 2.
    Folkman J. (1974) Tumor angiogenesis. Adv. Cancer Res. 19, 331–358.PubMedCrossRefGoogle Scholar
  3. 3.
    Battegay, E. J. (1995) Angiogenesis: mechanistic insights, neovascular diseases, and therapeutic prospects. J. Mol. Med. 73, 333–346.PubMedCrossRefGoogle Scholar
  4. 4.
    Zabel, D. D., Feng, J. J., Scheuenstuhl, H., Hunt, T. K., and Hussain, M. Z. (1996) Lactate stimulation of macrophage-derived angiogenic activity is associated with inhibition of poly(ADP-ribose) synthesis. Lab. Invest. 74, 644–649.PubMedGoogle Scholar
  5. 5.
    Adair, T. H., Gay, W. J., and Montani, J-P. (1990) Growth regulation of the vascular system: evidence for a metabolic hypothesis. Am. J. Physiol. 259, R393–R404.PubMedGoogle Scholar
  6. 6.
    Hunt, T. K. and Pai, M. P. (1972) The effect of varying ambient oxygen tensions on wound metabolism and collagen synthesis. Surg. Gynecol. Obstet. 135, 561–567.PubMedGoogle Scholar
  7. 7.
    Hopf, H. and Hunt, T. (1992) The role of oxygen in wound repair and wound infection, in Musculoskeletal Infection (Esterhai, J., Gristina, A., and Poss, R., eds.), American Academy of Orthopaedic Surgeons, Park Ridge, pp. 329–339.Google Scholar
  8. 8.
    Hunt, T. K. (1990) Basic principles of wound healing. J. Trauma 30, S 122–S 128.CrossRefGoogle Scholar
  9. 9.
    Hunt, T. K., Twomey, P., Zederfeldt, B., and Dunphy, J. E. (1967) Respiratory gas tensions and pH in healing wounds. Am. J. Surg. 114, 302.PubMedCrossRefGoogle Scholar
  10. 10.
    Silver, I. A. (1969) Measure of oxygen tension in healing tissue. Prog. Resp. Res. 3, 124–135.Google Scholar
  11. 11.
    Goodson, W. H., Andrews, W. S., Thakral, K. K., and Hunt, T. K. (1979) Wound oxygen tension of large vs small wounds in man. Surg. Forum 30, 92–95.PubMedGoogle Scholar
  12. 12.
    Ferrara, N. and Davis-Smyth, T. (1997) Biology of vascular endothelial growth factor. Endocr. Rev. 18, 4–25.PubMedCrossRefGoogle Scholar
  13. 13.
    Knighton, D. R., Hunt, T. K., Scheuenstuhl, H., Halliday, B. J., Werb, Z., and Banda, M. J. (1983) Oxygen tension regulates the expression of angiogenesis factor by macrophages. Science 221, 1283–1285.PubMedCrossRefGoogle Scholar
  14. 14.
    Sabri, M. N., DiSciascio, G., Cowley, M. J., Alpert, D., and Vetrovec, G. W. (1991) Coronary collateral recruitment: functional significance and relation to rate of vessel closure. Am. Heart J. 121, 876–880.PubMedCrossRefGoogle Scholar
  15. 15.
    Aiello, L. P., Avery R. L., Arrigg, P. G., Keyt, B. A., Jampel, H. D., Shah, S. T., et al. (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders [see comments]. N. Engl. J. Med. 331, 1480–1487.PubMedCrossRefGoogle Scholar
  16. 16.
    Shweiki, D., Neeman, M., Itin, A., and Keshet, E. (1995) Induction ofvascular endothelial growth factor expression by hypoxia and by glucose deficiency in multicell spheroids: implications for tumor angiogenesis. Proc. Natl. Acad. Sci. USA 92, 768–772.PubMedCrossRefGoogle Scholar
  17. 17.
    Miller, J. W., Adamis, A. P., Shima, D. T., D’Amore, P. A., Moulton, R. S., O’Reilly, M. S., et al. (1994) Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model. Am. J. Pathol. 145, 574–584.PubMedGoogle Scholar
  18. 18.
    Shima, D. T., Adamis, A. P., Ferrara, N., Yeo, K. T., Yeo, T. K., Allende, R., et al. (1995) Hypoxic induction of endothelial cell growth factors in retinal cells: identification and characterization of vascular endothelial growth factor (VEGF) as the mitogen. Mol. Med.1, 182–193.PubMedGoogle Scholar
  19. 19.
    Constant, J. S., Feng, J. J., Zabel, D. D., Yuan, H., Suh, D. Y., Scheuenstuhl, A. B., et al. (1997) Lactate stimulates macrophages to release vascular endothelial growth factor, unpublished.Google Scholar
  20. 20.
    Hussain, M. Z., Ghani, Q. P., and Hunt, T. K. (1989) Inhibition of prolyl hydroxylase by poly(ADP-ribose) and phosphoribosyl-AMP. J. Biol. Chem. 264, 7850–7855.PubMedGoogle Scholar
  21. 21.
    Ghani, Q. P., Hussain, M. Z., Jincai, Z., and Hunt, T. K. (1992) Control ofprocollagen gene transcription and prolyl hydroxylase activity by poly(ADP–ribose), in ADP-Ribosylation Reactions (Poirier, G. G. and Moreau, P., eds.), New York: Springer Verlag, 211–217.CrossRefGoogle Scholar
  22. 22.
    Althaus, F. and Richter, C. (1987) ADP–ribosylation of proteins: enzymology and biological significance. Mol. Biol. Biochem. Biophys. 37, 3–230.CrossRefGoogle Scholar
  23. 23.
    Satoh, M. S., Poirier, G. G., and Lindhal, T. (1993) NAD+ dependent repair of damaged DNA by by human cell extracts. J. Biol. C’hem. 268, 5480–5487.Google Scholar
  24. 24.
    Okazaki, I. J. and Moss, J. (1996) Mono-ADP-ribosylation: a reversible posttranslational modification of proteins. Adv. Pharm. 35, 247–280.CrossRefGoogle Scholar
  25. 25.
    Loetscher, P., Alvares-Gonzales, R., and Althaus, F. R. (1987) Poly(ADP-ribose) may signal changing metabolic conditions to the chromatin of mammalian cells. Proc. Natl. Acad. Sci. USA 84, 1286–1289.PubMedCrossRefGoogle Scholar
  26. 26.
    Lu, D., Maulik, N., Moraru, I. I., Kreutzer, D. L., Das, D. K. (1993) Molecular adaptation of vascular endothelial cells to oxidative stress. Am. J. Physiol. 264, C715–C722.Google Scholar
  27. 27.
    Goldberg, M. A. and Schneider, T. J. (1994) Similarities between the oxygen-sensing mechanisms regulating the expression of vascular endothelial growth factor and erythropoietin. J. Biol. Chem. 269, 4355–4359.PubMedGoogle Scholar
  28. 28.
    Minchenko, A., Salceda, S., Bauer, T., and Caro, J. (1994) Hypoxia regulatory elements of the human vascular endothelial growth factor gene. Cell. Mol. Biol. Res. 40(1), 35–39.PubMedGoogle Scholar
  29. 29.
    Wang, G. L. and Semenza, G. L. (1993) Characterization of hypoxia-inducible factor ( 1) and regulation of DNA binding activity by hypoxia. J. Biol. Chem. 268, 21,513–21,518.Google Scholar
  30. 30.
    Finkenzeller, G., Technau, A., and Marme, D. (1995) Hypoxia-induced transcription of the vascular endothelial growth factor gene is independent of functional AP-1 transcription factor. Biochem. Biophys. Res. Commun. 208, 432–439.PubMedCrossRefGoogle Scholar
  31. 31.
    Mukhopadhyay, D., Tsiokas, L., Zhou, X., Foster, D., Brugge, J., and Sukhatme, V. (1995) Hypoxic induction of human endothelial growth factor expression through c-Src activation. Nature 375, 577–581.PubMedCrossRefGoogle Scholar
  32. 32.
    Szabo, C., Zingarelli, B., O’Connor, M., and Salzman, A. L. (1996) DNA strand breakage, activation of poly(ADP-ribose) synthetase, and cellular energy depletion are involved in the cytotoxicity in macrophages and smooth muscle cells exposed to peroxynitrite. Proc. Natl. Acad. Sci. USA 93,1753–1758.PubMedCrossRefGoogle Scholar
  33. 33.
    Leibovich, S. J. (1997) Communication at 1997 Gordon Conference.Google Scholar
  34. 34.
    Argiles, J. M. and Lopez-Soriano, F. J. (1990) Why do cancer cells have such a high glycolytic rate?Med. Hypotheses 32, 151–155.CrossRefGoogle Scholar
  35. 35.
    Burch, H. and VonDippe, P. (1964) Pyridine nucleotides in developing rat liver. J. Biol. Chem. 239,1898,1899.Google Scholar
  36. 36.
    Ferris, G. and Clark, J. (1971) Nicotinamide nucleotide synthesis in regenerating liver. Biochem. J. 121, 655–662.PubMedGoogle Scholar
  37. 37.
    Stubbs, M., Rodrigues, L., Howe, F., Wang, J., Jeong, K.-S., Veech, R., et al. (1994) Metabolic consequences of a reversed pH gradient in rat tumors. Cancer Res. 54, 4011–4016.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • M. Zamirul Hussain
  • Q. Perveen Ghani
  • John J. Feng
  • Thomas K. Hunt

There are no affiliations available

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