The inhibitory effects of recombinant plasminogen kringle 1-3 on the neovascularization of rabbit cornea induced by angiogenin, bFGF, and VEGF

Exp Mol Med. 1999 Dec 31;31(4):203-9. doi: 10.1038/emm.1999.33.


Angiostatin is a potent angiogenesis inhibitor that is composed of the first four kringles of plasminogen fragment. Angiostatin with one less kringle molecule (kringle 1 to 3) was recently demonstrated to be an effective angiogenic inhibitor. To determine whether recombinant plasminogen kringle 1-3 (rPK1-3) can inhibit the corneal neovascularization induced by potent angiogenic factors; angiogenin, bFGF, or VEGF, hydron polymer discs each containing 2.0 microg of angiogenin, 500 ng of bFGF, or 500 ng of VEGF respectively were implanted into the corneal stroma of 138 rabbit eyes, and then discs each containing 10 microg, 12.5 microg, 20 microg or 30 microg of rPK1-3 were implanted randomly. Discs containing phosphate buffered saline were also implanted as a control. The angiogenesis score on number and length of newly formed vessels on the each of the rabbit's cornea were recorded daily by two observers (blinded). The treated corneas were also examined histologically. Recombinant PK1-3 treated corneas showed less neovascularization induced by all angiogenic factors (p < 0.05). and the extent of inhibition of neovascularization was proportional to the concentration of rPK1-3 (p < 0.05). Histologic examination showed leukocyte infiltration into the corneal stroma on the PBS treated eyes whereas rPK1-3 treated eyes showed only traces of leukocytes. These results of the effective rPK1-3 inhibition of corneal neovascularization induced by angiogenin, bFGF, or VEGF suggest that this angiostatin related fragment, rPK1-3, may be useful in the treatment of various neovascular diseases.

MeSH terms

  • Angiogenesis Inhibitors / genetics
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Chick Embryo
  • Chorion / blood supply
  • Chorion / drug effects
  • Cornea / blood supply*
  • Cornea / drug effects
  • Cornea / pathology
  • Endothelial Growth Factors / pharmacology
  • Fibroblast Growth Factor 2 / pharmacology
  • Kringles / genetics
  • Lymphokines / pharmacology
  • Microscopy / methods
  • Neovascularization, Pathologic / drug therapy*
  • Plasminogen / genetics*
  • Plasminogen / pharmacology*
  • Rabbits
  • Recombinant Proteins / genetics
  • Recombinant Proteins / pharmacology
  • Ribonuclease, Pancreatic / pharmacology
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • Angiogenesis Inhibitors
  • Endothelial Growth Factors
  • Lymphokines
  • Recombinant Proteins
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Fibroblast Growth Factor 2
  • Plasminogen
  • angiogenin
  • Ribonuclease, Pancreatic