Analysis of the mechanism of angiogenesis regulated by fibrinolytic factors

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Double gene deficient mouse of the fibrinolytic factors, which lost two kinds of fibrinolytic genes, was produced by crossing single gene deficient mouse of fibrinolytic factor which we have already established. Double gene deficient mice produced were mouse which lost u-PA and u-PAR genes (u-PA/u-PAR double knockout mouse), that lost u-PA and t-PA genes (u-PA/t-PA double knockout mouse), that lost α2-AP and u-PA genes (α2-AP/u-PA double knockout mouse) and th at lost α2-AP and t-PA genes (α2-A P/t-PA double knocktout mouse). The present study was performed in accordance with the institutional guidelines.When the hemispherical capsule, which had many holes, was transplanted to subcutaneous of u-PA/t-PA double knockout mouse, the MMP-2 activity of the granulation tissue, which adhered out side of capsule, was significantly lower than the wild-type mouse. On the other hand, the MMP-2 activity of the granulation tissue, which proliferated in the capsule, was significantly higher than the wild-type mouse.The vascular endothelial cell in granulation tissue which adhered to the capsule in u-PA/t-PA double knockout mouse was fewer than the wild type mouse, and it was indicated that both u-PA and t-PA were involved in the angiogenesis. Since plasminogen is the substrate for u-PA and t-PA, it is suggested that the plasminogen is important for the angiogenesis. Therefore, regulation of expression of the plasminogen gene was examined using the primary cultured liver cell. In the low-density culture, the expression of plasminongen mRNA was decreased. However, in the high-density culure where one hepatocyte attached to another, decrease in plasminogen mRNA was not observed. Therefore, it is confirmed that the stimulation by cell-cell contact may play an important role to maintain the expression of plasminongen mRNA in hepatocytes.