Abstract
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.
Highlights
Angiogenesis is essential in tissue reproduction, development, and wound repair
Chorioallantoic membrane assay After 3 days of the application of thermonox coverslips with basic fibroblastic growth factor (bFGF) and with or without recombinant plasminogen kringle 1-3 (rPK1-3) (Figure 1), embryos and chorioallantoic membrane assay (CAM) were observed with stereomicroscope
On the third day of post-implantation of angiogenin, the eyes treated with rPK1-3 had less angiogenesis than the eyes treated with PBS (p < 0.05, Figure 2)
Summary
Angiogenesis is essential in tissue reproduction, development, and wound repair. angiogenesis is associated with pathogenesis of numerous eye diseases; loss of visual acuity, neovascular glaucoma, diabetic retinopathy, chemical burns and viral infections of the cornea (Epstein et al, 1987). Angiostatin purified from serum and urine of mice bearing a murine Lewis lung carcinoma has been demonstrated to be one of the potent angiogenesis inhibitors specially that targets proliferating endothelial cells (O’Reilly et al, 1994; O’Reilly et al, 1996). Angiostatin contains the first four out of five repeating loop of plasminogen molecule known as the kringle domain. Each kringle is composed of 80 amino acids polypeptide chain linked by disulfide bonds at an end and at midregion forming two, an inner and an outer loop structures. In vitro, it inhibits endothelial cell growth, but not proliferation of other cell types, including tumor cells. Small fragments of angiostatin have been demonstrated to display differential
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