REDUCED TRANSPLANT ARTERIOSCLEROSIS IN PLASMINOGEN-DEFICIENT MICE

Recent gene targeting studies indicate that the plasminogen system is implicated in cell migration and matrix degradation during arterial ne ointima formation and atherosclerotic aneurysm formation. This study e xamined whether plasmin proteolysis is involved in accelerated posttra nsplant arteriosclerosis (graft arterial disease). Donor carotid arter ies from wild-type B10.A2R mice were transplanted into either plasmino gen wild-type (Plg(+/+)) or homozygous plasminogen-deficient (Plg(-/-) ) recipient mice with a genetic background of 75% C57BL/6 and 25% 129. Within 15 d after allograft transplantation, leukocytes and macrophag es infiltrated the graft intima in Plg(+/+) and Plg(-/-) recipient mic e to a similar extent. In Plg(+/+) recipients, the elastic laminae in the transplant media exhibited breaks through which macrophages infilt rated before smooth muscle cell proliferation, whereas in Plg(-/-) rec ipients, macrophages failed to infiltrate the transplant media which r emained structurally more intact. After 45 d of transplantation, a mul tilayered smooth muscle cell-rich transplant neointima developed in Pl g(+/+) hosts, in contrast to Plg(-/-) recipients, in which the transpl ants contained a smaller intima, predominantly consisting of leukocyte s, macrophages, and thrombus. Media necrosis, fragmentation of the ela stic laminae, and adventitial remodeling were more pronounced in Plg(/+) than in Plg-'- recipient mice. Expression of the plasminogen activ ators (PA), urokinase-type PA (u-PA) and tissue-type PA (t-PA), and ex pression of the matrix metalloproteinases (MMPs), MMP-3, MMP-9, MMP-12 and MMP-13, were significantly increased within 15 d of transplantati on when cells actively migrate. These data indicate that plasmin prote olysis plays a major role in allograft arteriosclerosis by mediating e lastin degradation, macrophage infiltration, media remodeling, medial smooth muscle cell migration, and formation of a neointina.