Angiogenesis pp 121-128 | Cite as

Angiogenic Mediators in Wound Healing

  • Luisa A. DiPietro
  • Nicholas N. Nissen
Part of the NATO ASI Series book series (NSSA, volume 298)


Angiogenesis is an essential component of normal wound repair. Neovascularization provides nutrient support to healing tissue, promotes granulation tissue formation, and assists in the clearance of debris. Despite the prominent role of angiogenesis in the repair process, the primary mediators of wound angiogenesis have been difficult to define. An abundance of potential angiogenic agonists and antagonists have been identified in healing wounds (Table I), suggesting that the net angiogenic stimulus relies upon a balance of positive and negative mediators. The identification of this rather plentiful number of candidate mediators seems to indicate that angiogenesis in wounds is regulated by a most redundant and complex mechanism.


Vascular Endothelial Growth Factor Basic Fibroblast Growth Factor Angiogenic Activity Vascular Endothelial Cell Growth Factor Wound Fluid 
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  1. Abraham J.A., Mergia, A., Whang, J., Turnolo, A., Friedman, J., Hjerrild, K.A., Gospodarowicz, D., and Fiddes, J.C., 1986, Nucleotide sequence of a bovine clone encoding the angiogenic protein basic fibroblast growth factor, Science 233:545–548.PubMedCrossRefGoogle Scholar
  2. Antoniades, H.N., Galanopoulos, T., Neville-Golden, J., Kiritsy, C.P., and Lynch, S.P., 1994, Expression of growth factor and receptor mRNAs in skin epithelial cells following acute cutaneous injury, Am. J. Pathol. 142:1099–1110.Google Scholar
  3. Arnold, F., West, D.C., Schofield, P.F., and Kumar, S., 1987, Angiogenic activity in human wound fluid, Int. J. Microcirc. Clin. Exp. 5:381–386.PubMedGoogle Scholar
  4. Banda, M.J., Knighton, D.R., Hunt, T.K., and Werb, Z., 1982, Isolation of a nonmitogenic angiogenesis factor from wound fluid, Proc. Natl. Acad. Sci. USA 79:7773–7777.PubMedCrossRefGoogle Scholar
  5. Bashkin, P., Doctrow, S., Klagsbrun, M., Svahn, C.M., Folkman, J., and Vlodavsky, I., 1989, Basic fibroblast growth factor binds to subendothelial extracellular matrix and is released by heparitinase and heparin-like molecules, Biochemistry 28:1737–1743.PubMedCrossRefGoogle Scholar
  6. Broadley, K., Aquino, A., Woodward, S., Buckley-Sturrock, A., Sato, Y., Rifkin, D.B., and Davidson, J.M., 1989, Monospecific antibodies implicate basic fibroblast growth factor in normal wound repair, Lab. Invest. 61:571–575.PubMedGoogle Scholar
  7. Brown, L.F., Kiang-Teck, Y., Berse, B., Yeo, T., Senger, D.R., Dvorak, H.F., and Van De Water, L., 1992, Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing, J. Exp. Med. 176:1375–1379.PubMedCrossRefGoogle Scholar
  8. Brunner, G., Nguyen, H., Gabrilove, J., Rifkin, D.B., and Wilson, E.L., 1993, Basic fibroblast growth factor expression in human bone marrow and peripheral blood cells, Blood 81:631–638.PubMedGoogle Scholar
  9. Dvonch, V.M., Murphey, R.J., Matsuoka, J., and Grotendorst, G., 1992, Changes in growth factor levels in human wound fluid, Surgery 112:18–23.PubMedGoogle Scholar
  10. Dvorak, H.F., Brown, L.F., Detmar, M., and Dvorak, A.M., 1995, Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis, Am. J. Path. 146:1029–1039.PubMedGoogle Scholar
  11. Ferrara, N., Houck, K., Jakeman, L., and Leung, D., 1992, Molecular and biological properties of the vascular endothelial growth factor family of proteins, Endocrine Rev. 13:18–32.Google Scholar
  12. Frank, S., Hubner, G., Breier, G., Longaker, M.R., Greenhalgh, D.G., and Werner, S., 1995, Regulation of vascular endothelial growth factor expression in cultured keratinocytes, J. Biol. Chem. 270:12607–12613.PubMedCrossRefGoogle Scholar
  13. Gajdusek, C.M., and Carbon, S., 1989, Injury-induced release of basic fibroblast growth factor from bovine aortic endothelium, J. Cell. Physiol. 139:570–579.PubMedCrossRefGoogle Scholar
  14. Gibran, N.S., Isik, F.F., Heimbach, D.M., and Gordon, D., 1994, bFGF in the early human burn wound. J. Surg. Res. 56:226–234.PubMedCrossRefGoogle Scholar
  15. Greenburg, G.B., and Hunt, T.K., 1978, The proliferative response in vitro of vascular endothelial and smooth muscle cells exposed to wound fluids and macrophages, J. Cell Physiol. 97:353–360.PubMedCrossRefGoogle Scholar
  16. Grayson L.S., Hansborough, J.F., Zapata-Sirvent, R.L., Dore, C.A., Morgan, J.L. and Nicolson, M.A., 1993, Quantitation of cytokine levels in skin graft donor site wound fluid, Burns 19:401–405.PubMedCrossRefGoogle Scholar
  17. Gupta, V.K., McNeil, P.L., Riegner, C., and Howdieshell, T.R., 1996, Vascular endothelial growth factor is a key mediator of omental angiogenesis, Surg. Forum 47:746–749.Google Scholar
  18. Hunt, T.K., Knighton, D.R., Thakral, K.K., Goodson, W.H. III, and Andrews, W.S., 1984, Studies on inflammation and wound healing: Angiogenesis and collagen synthesis stimulated in vivo by resident and activated wound macrophages, Surgery 96:48–54.PubMedGoogle Scholar
  19. Katz, M.H., Alvarez, A.F., Kirsner, R.S., Eaglstein, W.H., and Falanga, V., 1991, Human wound fluid from acute wounds stimulates fibroblast and endothelial cell growth, J. Amer. Acad. Dermatol. 25:1054–1058.CrossRefGoogle Scholar
  20. 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
  21. Kurita, Y., Tsuboi, R., Ucki, R., Rifkin, D.B., and Ogawa, H., 1992, Immunohistochemical localization of basic fibroblast growth factor in wound healing sites of mouse skin, Arch. Dermatol Res. 284:193–197.PubMedCrossRefGoogle Scholar
  22. Leibovich, S.J., and Ross, R., 1975, The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum, Am. J. Pathol. 78:71–91.PubMedGoogle Scholar
  23. Muthukrishnan, L., Warder, E., and McNeil, P., 1991, Basic fibroblast growth factor is efficiently released from a cytosolic storage site through plasma membrane disruptions of endothelial cells, J. Cell. Physiol. 148:1–16.PubMedCrossRefGoogle Scholar
  24. Nissen, N.N., R.L. Gamelli, P.J. Polverini, and DiPietro, L.A., 1996, Basic fibroblast growth factor mediates angiogenic activity in early surgical wounds, Surgery 119:457–465.PubMedCrossRefGoogle Scholar
  25. Rappolee, D.A., Mark, D., Banda, M.J., and Werb, Z., 1988, Wound macrophages express TGF-a and other growth factors in vivo: analysis by mRNA phenotyping, Science 241:708–712.PubMedCrossRefGoogle Scholar
  26. Schweiki, D., Itin, A., Soffer, D., and Keshet, E., 1992, Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis, Nature 359:843–845.CrossRefGoogle Scholar
  27. Thakral, K.K., Goodson, W.H. III, and Hunt, T.K., 1979, Stimulation of wound blood vessel growth by wound macrophages, J. Surg. Res. 26:430–436.PubMedCrossRefGoogle Scholar
  28. Villaschi, S., and Nicosia, R.F., 1993, Angiogenic role of endogenous basic fibroblast growth factor released by rat aorta after injury, Am. J. Pathol. 143:181–190.PubMedGoogle Scholar
  29. Werner, S., Peters, K.G., Longaker, M.T., Fuller-Pace, F., Banda, M.J., and Williams, L.T., 1992, Large induction of keratinocyte growth factor expression in the dermis during wound healing, Proc. Natl. Acad Sci. USA 89:6896–6900.PubMedCrossRefGoogle Scholar
  30. Werner, S., Breeden, M., Hübner, G., Greenhalgh, D.G., and Longaker, M.T., 1994, Induction of keratinocyte growth factor expression is reduced and delayed during wound healing in the genetically diabetic mouse, J. Invest. Dermatol. 103:469–473.PubMedCrossRefGoogle Scholar
  31. Whitby, D.J., and Ferguson, M.W., 1991, Immunohistochemical localization of growth factors in fetal wound healing. Developmental Biol. 147:207–215.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Luisa A. DiPietro
    • 1
  • Nicholas N. Nissen
    • 1
  1. 1.Burn and Shock Trauma Institute, Department of Surgery, LoyolaUniversity Medical CenterMaywoodUSA

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