Growth Control in Capillary Endothelium

  • Judah Folkman
Part of the Developmental Biology book series (DEBO, volume 3)


A network of capillary blood vessels supplies the nutritional needs of every part of the body. The endothelial cells lining these capillaries comprise a tissue of approximately 2 kg in a 70-kg human. These endothelial cells perform a variety of metabolic, immunological, and hemostatic functions (Ryan and Ryan, 1981; Pober et al., 1983; Loskutoff and Levin, 1984), but they rarely proliferate. Their rate of replication is usually so low that turnover times are measured in thousands of days (Folkman and Cotran, 1976; Denekamp and Hobson, 1984). By contrast, the turnover of intestinal mucosa is approximately 3 days and that of bone marrow about 5 days. However, with an appropriate stimulus, capillary endothelial cells can begin rapid proliferation and achieve turnover times almost as fast as bone marrow cells. Capillary endothelial cells proliferate most actively during angiogenesis, i.e., when new capillaries are being formed.


Mast Cell Fibroblast Growth Factor Chick Embryo Angiogenic Factor Capillary Endothelial Cell 


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  1. Ausprunk, D. H., and Folkman, J. ,1977, Migration and proliferation of endothelial cells in pre formed and newly formed blood vessels during tumor angiogenesis, Microvasc. Res. 14:53–65.PubMedCrossRefGoogle Scholar
  2. Azizkhan, R. G., Azizkhan, J. C, Zetter, B. R., and Folkman, J., 1980, Mast cell heparin stimulates migration of capillary endothelial cells in vitro, J. Exp. Med. 152:931–944.PubMedCrossRefGoogle Scholar
  3. Baird, A., Mormede, P., and Bohlen, P., 1985, Immunoreactive fibroblast growth factor in cells of peritoneal exudate suggests its identity with macrophage-derived growth factor, Biochem. Biophys. Res. Commun. 126:358–364.PubMedCrossRefGoogle Scholar
  4. Banda, M. J., Knighton, D. R., Hunt, T. K., and Werb, Z., 1982, Isolation of a nonmitogenic angiogenic factor from wound fluid, Proc. Natl. Acad. Sci. USA 79:7773–7777.PubMedCrossRefGoogle Scholar
  5. Bär, T., and Wolff, J. R., 1972, The formation of capillary basement membranes during internal vascularization of the rat’s cerebral cortex, Z. Zeilforsch. 133:231–248.CrossRefGoogle Scholar
  6. Barritault, D., Arruti, C, and Courtois, Y., 1981, Is there a ubiquitous growth factor in the eye? Proliferation induced in different cell types by eye-derived growth factors, Differentiation 18:29–42.PubMedCrossRefGoogle Scholar
  7. BenEzra, D., 1978, Neovasculogenic ability of prostaglandins, growth factors, and synthetic chemoattractants, Am. J. OphthaJmol. 86:455–461.Google Scholar
  8. Bohlen, P., Baird, A. ,Esch, F. ,Ling, N., and Gospodarowicz, D., 1984, Isolation and partial molecular characterization of pituitary fibroblast growth factor, Proc. Natl. Acad. Sci. USA 81:5364–5368.PubMedCrossRefGoogle Scholar
  9. Brem, H., and Folkman, J. ,1975, Inhibition of tumor angiogenesis mediated by cartilage, J. Exp. Med. 141:427–439.PubMedCrossRefGoogle Scholar
  10. Castellot, J. J. ,Jr., Karnovsky, M. J., and Spiegelman, B. M., 1982, Differentiation dependent stimulation of neovascularization and endothelial cell Chemotaxis by 3T3 adipocytes, Proc. Natl. Acad. Sci. USA 79:5597–5601.PubMedCrossRefGoogle Scholar
  11. Courty,). ,Loret, C., Moenner, M., Chevallier, B., Lagente, O., Courtois, Y., and Barritault, D., 1985, Bovine retina contains three growth factor activities with different affinities for heparin: Eyederived growth factors, I, II, III, Biochimie 67:265–269.PubMedCrossRefGoogle Scholar
  12. Crum, R., Szabo, S. ,and Folkman, J. ,1985, A new class of steroids inhibits angiogenesis in the presence of heparin or a heparin fragment, Science 230:1375–1378.PubMedCrossRefGoogle Scholar
  13. D’Amore, P. A., and Klagsbrun, M., 1984, Endothelial cell mitogens derived from retina and hypothalamus: Biochemical and biological similarities, J. Cell Biol. 99:1545–1549.PubMedCrossRefGoogle Scholar
  14. D’Amore, P. A., Glaser, B. M., Brunson, S. K., and Fenselau, A. H., 1981, Angiogenic activity from bovine retina: Partial purification and characterization, Proc. Natl. Acad. Sci. USA 78:3068–3072.PubMedCrossRefGoogle Scholar
  15. Davidson, J. M., Klagsbrun, M., Hill, K. E., Buckley, A., Sullivan, R., Brewer, P. S., and Woodward, S. C., 1985, Accelerated wound repair, cell proliferation, and collagen accumulation are produced by a cartilage-derived growth factor, J. Cell Biol. 100:1219–1227.PubMedCrossRefGoogle Scholar
  16. Denekemp, J. ,and Hobson, B., 1984, Endothelial proliferation in normal tumour blood vessels, Microvasc. Res. 27(3):388.Google Scholar
  17. Eisenstein, R., Sorgente, N., Soble, L. W., Miller, A. ,and Kuettner, K. E., 1973, The resistance of certain tissues to invasion: Penetrability of explanted tissues by vascularized mesenchyme, Am. J. Pathol. 73:765–774.PubMedGoogle Scholar
  18. Esch, F., Ling, N., Bohlen, P., Baird, A., Benoit, R., and Guillemin, R., 1984, Isolation and characterization of the bovine hypothalamic corticotropin-releasing factor, Biochem. Biophys. Res. Commun. 122:899–905.PubMedCrossRefGoogle Scholar
  19. Esch, F., Baird, A., Ling, N., Ueno, N., Hill, F., Denoroy, L., Klepper, R., Gospodarowicz, D., Bohlen, P., and Guillemin, R., 1985, Primary structure of bovine pituitary basic fibroblast growth factor (FGF) and comparison with the amino-terminal sequence of bovine brain acidic FGF, Proc. Natl. Acad. Sci. USA 82:6507–6511.PubMedCrossRefGoogle Scholar
  20. Fenselau, A. ,and Mello, R. J. ,1976, Growth stimulation of cultured endothelial cells by tumor cell homogenates, Cancer Res. 36:3269–3273.PubMedGoogle Scholar
  21. Fett, J. W., Strydom, D. S., Lobb, R. R., Alderman, E. M., Bethune, J. L., Riordan, J. F. ,and Vallee, B. L. ,1985, Lysozyme: A major secretory product of a human colon carcinoma cell line, Bio chemistry 24:965–975.Google Scholar
  22. Folkman, J. ,1972, Anti-angiogenesis: New concept for therapy of solid tumors, Ann. Surg. 175:409–416.PubMedCrossRefGoogle Scholar
  23. Folkman, J., 1985, Tumor angiogenesis, Adv. Cancer Res. 43:175–203.PubMedCrossRefGoogle Scholar
  24. Folkman, J. ,and Cotran, R., 1976, Relation of vascular proliferation to tumor growth, Int. Rev. Exp. Pathol. 16:207–248.PubMedGoogle Scholar
  25. Folkman, J., and Haudenschild, C., 1980, Angiogenesis in vitro, Nature (Lond.) 288:551–556.CrossRefGoogle Scholar
  26. Folkman, J., Merler, E., Abernathy, C., and Williams, G., 1971, Isolation of a tumor factor responsible for angiogenesis, J. Exp. Med. 133:275–288.PubMedCrossRefGoogle Scholar
  27. Folkman, J. ,Haudenschild, C. C., and Zetter, B. R., 1979, Long-term culture of capillary endothelial cells, Proc. Natl. Acad. Sci. USA 76(10):5217–5221.CrossRefGoogle Scholar
  28. Folkman, J. ,Langer, R., Linhardt, R., Haudenschild, C., and Taylor, S., 1983a, Angiogenesis inhibition and tumor regression caused by heparin or a heparin fragment in the presence of cortisone, Science 221:719–725.PubMedCrossRefGoogle Scholar
  29. Folkman, J., Taylor, S. ,and Spillberg, C, 1983b, The role of heparin in angiogenesis, in: Development of the Vascular System ,Ciba Foundation Symposium 100, pp. 132–149, Pitman, London.Google Scholar
  30. Form, D. M. ,and Auerbach, R., 1983, PGE2 and angiogenesis (41548), Proc. Soc. Exptl. Biol. Med. 172:214–218.Google Scholar
  31. Fournier, G. A., Lutty, G. A. ,Watt, S. ,Fenselau, A. ,and Patz, A., 1981, A corneal micropocket assay for angiogenesis in the rat eye, Invest. Ophthalmol. Vis. Sci. 21:351–354.PubMedGoogle Scholar
  32. Gimbrone, M. A., Jr., Leapman, S. B., Cotran, R. S., and Folkman, J. ,1972, Tumor dormancy in vivo by prevention of neovascularization, J. Exp. Med. 136:261–276.PubMedCrossRefGoogle Scholar
  33. Gimbrone, M. A. ,Jr., Cotran, R. S., Leapman, S. B., and Folkman, J., 1974, Tumor growth and neovascularization: An experimental model using the rabbit cornea, J. Natl. Cancer Inst. 52:413–427.PubMedGoogle Scholar
  34. GosDodarowicz. D.. Bialecki, H., and Greenburg, G., 1978, Purification of the fibroblast growth factor activity from bovine brain, J. Biol. Chem. 253(10):3736–3743.Google Scholar
  35. Gospodarowicz, D., Cheng, J. ,Lui, G. M. ,Baird, A. ,and Bohlen, P., 1984, Isolation of brain fibroblast growth factor by heparin-Sepharose affinity chromatography: Identity with pituitary fibroblast growth factor, Proc. Natl. Acad. Sci. USA 81:6963–6967.PubMedCrossRefGoogle Scholar
  36. Gospodarowicz, D., Cheng, J., Lui, G. M., Baird, A., Esch, F. ,and Bohlen, P., 1985, Corpus luteum angiogenic factor is related to fibroblast growth factor, Endocrinology 117:2283–2391.CrossRefGoogle Scholar
  37. Hauschka, P. V., Iafrati, S. E., Doleman, S. E., Sullivan, R. C, and Klagsbrun, M. ,1985, Resolution of distinct classes of bone matrix-derived cell growth factors by heparin affinity chromatography, Calcif. Tissue Int. 37:7a.Google Scholar
  38. Kalebic, T., Garbisa, S., Glaser, B., and Liotta, L. A. ,1983, Basement membrane collagen degradation by migrating endothelial cells, Science 221:281–283.PubMedCrossRefGoogle Scholar
  39. Kaminski, M. ,Kaminska, G., and Majewski, S., 1978, Inhibition of new blood vessel formation in mice by systemic administration of human rib cartilage extract, Experientia 34:490–491.PubMedCrossRefGoogle Scholar
  40. Keegan, A. ,Hill, C., Kumar, S., Phillips, P., Schor, A., and Weiss, J., 1982, Purified tumour angiogenesis factor enhances proliferation of capillary, but not aortic, endothelial cells in vitro, J. Cell Sci. 55:261–276.PubMedGoogle Scholar
  41. Kessler, D. A., Langer, R. S., Pless, N. A. ,and Folkman, J., 1976, Mast cells and tumor angiogenesis, Int. J. Cancer 18:703–709.PubMedCrossRefGoogle Scholar
  42. Klagsbrun, M. ,and Shing, Y. ,1985, Heparin affinity of anionic and cationic capillary endothelial cell growth factors: Analysis of hypothalamus-derived growth factors (HDGF) and fibroblast growth factors (FGF), Proc. Natl. Acad. Sci. USA 82:805–809.PubMedCrossRefGoogle Scholar
  43. Klagsbrun, M. ,and Smith, S., 1980, The purification of a growth factor from bovine cartilage, J. Biol. Chem. 255:10859–10866.PubMedGoogle Scholar
  44. Klagsbrun, M., Knighton, D., and Folkman, J., 1976, Tumor angiogenesis activity in cells grown in tissue culture, Cancer Res. 36:110–114.PubMedGoogle Scholar
  45. Kumar, S., West, D., Daniel, M., Hancock, A., and Carr, T., 1983, Human lung tumour cell line adapted to grow in serum-free medium secretes angiogenesis factor, Int. J. Cancer 32:461–464.PubMedCrossRefGoogle Scholar
  46. Kurachi, K., Davie, E. W., Strydom, D. J., Riordan, J. F., and Vallee, B. L., 1985, Sequence of the cDNA and gene for angiogenin, a human angiogenesis factor, Biochemistry 24:5493–5499.CrossRefGoogle Scholar
  47. Langer, R., and Folkman, J., 1976, Polymers for the sustained release of proteins and other macromolecules, Nature (Lond.) 263:797–800.CrossRefGoogle Scholar
  48. Langer, R., Brem, H., Falterman, K., Klein, M., and Folkman, J., 1976, Isolation of a cartilage factor which inhibits tumor neovascularization, Science 193:70–72.PubMedCrossRefGoogle Scholar
  49. Langer, R., Conn, H., Vacanti,J., Haudenschild, C, and Folkman,J., 1980, Control of tumor growth in animals by infusion of an angiogenesis factor, Proc. Natl. Acad. Sci. USA 77:4331–4335.PubMedCrossRefGoogle Scholar
  50. Larsen, A. K., Lund, D. P., Langer, R., and Folkman, J., 1986, Oral heparin results in the appearance of heparin fragments in the plasma of rats, Proc. Natl. Acad. Sci. USA 83:2964–2968.PubMedCrossRefGoogle Scholar
  51. Lobb, R. R., and Fett, J. W., 1984, Purification of 2 distinct growth factors from bovine neural tissue by heparin affinity chromatography, Biochemistry 23(26):6295–6298.PubMedCrossRefGoogle Scholar
  52. Lobb, R., Sasse, J., Sullivan, R., Shing, Y., D’Amore, P., Jacobs, J., and Klagsbrun, M., 1986, Purification and characterization of heparin-binding endothelial cell growth factors, J. Biol. Chem. 261(4):1924–1928.PubMedGoogle Scholar
  53. Loskutoff, D. J., and Levin, E., 1984, Properties of plasminogen activators produced by endothelial cells, in: Biology of Endothelial Cells (E. A. Jaffe, ed.), pp. 200–208, Martinus Nijhoff, Boston.CrossRefGoogle Scholar
  54. Maciag, T., Cerundolo, Ilsley, S., Kelley, P. R., and Forand, R., 1979, An endothelial cell growth factor from bovine hypothalamus: Identification and partial characterization, Proc. NatJ. Acad. Sci. USA 76:5674–5678.CrossRefGoogle Scholar
  55. Maciag, T., Mehlman, T., Friesel, R., and Schreiber, A. ,1984, Heparin binds endothelial cell growth factor, the principal endothelial cell mitogen in bovine brain, Science 225:932–935.PubMedCrossRefGoogle Scholar
  56. Madri, J. A., and Williams, S. K., 1983, Capillary endothelial cell cultures: Phenotypic modulation by matrix components, J. Cell Biol. 97:153–165.PubMedCrossRefGoogle Scholar
  57. Moscatelli, D., Gross, J. L., and Rifkin, D. B., 1981, Angiogenic factors stimulate plasminogen activator and collagenase production by capillary endothelial cells, J. Cell Biol. 91:201a.CrossRefGoogle Scholar
  58. Murray, J. B., Brown, L., Langer, R., and Klagsbrun, M., 1983, A micro sustained release system for epidermal growth factor, In Vitro 19(10):743–748.PubMedCrossRefGoogle Scholar
  59. Muthukkaruppan, V., and Auerbach, R., 1979, Angiogenesis in the mouse cornea, Science 205:1416–1417.PubMedCrossRefGoogle Scholar
  60. Peterson, H.-L, 1979, Tumor blood flow compared with normal tissue blood flow, in: Tumor Blood Circulation Angiogenesis, Vascular Morphology and Blood Flow of Experimental Human Tumors, pp. 103–135, CRC Press, Boca Raton, Florida.Google Scholar
  61. Phillips, P., Steward, J. K., and Kumar, S., 1976, Tumour angiogenesis factor (TAF) in human and animal tumours, Int. J. Cancer 17:549–558.PubMedCrossRefGoogle Scholar
  62. Pober, J., Collins, T., Gimbrone, M. A. ,Jr., Cotran, R., Gitlin, J. D., Fiers, W., Clayberger, C., Krensky, A., Burakoff, S., and Reiss, C. S., 1983, Lymphocytes recognize human vascular endothelial and dermal fibroblast la antigens induced by recombinant immune interferon, Nature (Lond.j 305:726–729.CrossRefGoogle Scholar
  63. Ryan, J. W., and Ryan, U., 1981, Endothelial metabolism, in: Microcirculation, Current Physiologic, Medical and Surgical Concepts (R. M. Effros, H. Schmid-Schonbein, and J. Ditzel, eds.) p. 147, Academic Press, New York.Google Scholar
  64. Schreiber, A. B., Kenney, J., Kowalski, J., Thomas, K. A., Gimenez-Gallego, G., Rios-Candelore, M., DiSalvo, J., Barritault, D., Courty, J., Courtois, Y., Moenner, M., Loret, C., Burgess, W. H., Mehlman, T., Friesel, R., Johnson, T., and Maciag, T., 1985, A unique family of endothelial cell polypeptide mitogens: The antigenic and receptor cross-reactivity of bovine endothelial cell growth factor, brain-derived acidic fibroblast growth factor, and eye-derived growth factor-II, J. Cell Biol. 101:1623–1626.PubMedCrossRefGoogle Scholar
  65. Shing, S., Folkman, J., Murray, J., and Klagsbrun, M., 1983, Purification by affinity chromatography on heparin-Sepharose of a growth factor that stimulates capillary endothelial cell proliferation, J. Cell Biol. 97:395a.Google Scholar
  66. Shing, Y., Folkman, J., Sullivan, R., Butterfield, C., Murray, J., and Klagsbrun, M., 1984, Heparin affinity: Purification of a tumor-derived capillary endothelial cell growth factor, Science 223:1296–1298.PubMedCrossRefGoogle Scholar
  67. Shing, Y., Folkman, J., Haudenschild, C, Lund, D., Crum, R., and Klagsbrun, M., 1985, Angiogenesis is stimulated by a tumor-derived endothelial cell growth factor, J. Cell. Biochem. 29:275–287.PubMedCrossRefGoogle Scholar
  68. Strydom, D. J. ,Fett, J. W., Lobb, R. R., Alderman, E. M., Bethune, J. L., Riordan, J. F., and Vallee, B. L. ,1985, Amino acid sequence of human tumor-derived angiogenin, 1985, Biochemistry 24:5486–5493.CrossRefGoogle Scholar
  69. Sullivan, R., and Klagsbrun, M. ,1985, Purification of cartilage-derived growth factor by heparin affinity chromatography, J. Biol. Chem. 260:2399–2403.PubMedGoogle Scholar
  70. Taylor, S., and Folkman, J. ,1982, Protamine is an inhibitor of angiogenesis, Nature (Lond.) 297:307–312.CrossRefGoogle Scholar
  71. Thomas, K. A., Rios-Candelore, M., and Fitzpatrick, S., 1984, Purification and characterization of acidic fibroblast growth factor from bovine brain, Proc. Natl. Acad. Sci. USA 81:357–361.PubMedCrossRefGoogle Scholar
  72. Thomas, K. A. ,Rios-Candelore, M. ,Gimenez-Gallego, G. ,DiSalvo, J. ,Bennett, C ,Rodkey, J. ,and Fitzpatrick, S., 1985, Pure brain-derived acidic fibroblast growth factor is a potent angiogenic vascular endothelial cell mitogen with sequence homology to interleukin 1, Proc. Natl. Acad. Sci. USA 82:6409–6413.PubMedCrossRefGoogle Scholar
  73. Tuan, D., Smith, S., Folkman, J., and Merler, E., 1973, Isolation of the non-histone proteins of rat Walker carcinoma 256: Their association with tumor angiogenesis, Biochemistry 12:3159– 3165.PubMedCrossRefGoogle Scholar
  74. Zetter, B. R., 1980, Migration of capillary endothelial cells is stimulated by tumour-derived factors, Nature (Lond.) 285:41–43.CrossRefGoogle Scholar
  75. Ziehe, M. ,and Gullino, P. M. ,1982, Angiogenesis and neoplastic progression in vitro, J. Natl. Cancer Inst. 69(2):483–487.Google Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • Judah Folkman
    • 1
    • 2
  1. 1.Department of SurgeryChildren’s HospitalBostonUSA
  2. 2.Department of Surgery, Department of Anatomy and Cellular BiologyHarvard Medical SchoolBostonUSA

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