Donor PAI-1 expression inhibits the intimal response of early allograft vascular disease

Background: The development of allograft vascular disease (AVD) may be related to altered expression of the fibrinolytic system. We determined the extent to which plasminogen activator inhibitor type 1 (PAI-1) expression in donor tissue influences intimal proliferation (IP) in a mouse model of AVD. Methods: We utilized an end-to-end abdominal aortic transplant model in mice to investigate the development of IP in 3 groups of 6 recipients. Group A (negative control) utilized C57BL/6J strain mice as both donors and recipients. In Groups B (positive control) and C, C57BL/6J mice were vessel donors and CBA/J mice were recipients. Both groups received intraperitoneal anti-CD4 and anti-CD8 monoclonal antibodies (250 mug/week for 5 weeks). Group C recipients, however, were transplanted with vessels from C57BL/6J PAI-1 knockout mice. Animals were killed at 50 days. Transplanted aortas were removed and intimal areas calculated using morphometric analysis. Results: Group A (mean intimal area 6,421 +/- 8,507 mum(2)) demonstrated very little IP in comparison to the other groups. IP was significantly higher in Group B (mean intimal area 56,357 +/- 35,629 mum(2)) than Group A (p = 0.008). Group C (mean intimal area 281,995 +/- 123,279 mum(2)) demonstrated significantly more intimal proliferation than either Groups A or B (vs B, p = 0.003; vs A, p < 0.001). The significance of these results is maintained if intimal thickness is measured as a stand-alone reference for the intimal response. Conclusions: Lack of PAI-1 expression in donor tissue greatly exaggerates the extent of IP after allogeneic transplantation and suggests that PAI-1 is important in limiting the early phase of AVD.