L. Moons et al., REDUCED TRANSPLANT ARTERIOSCLEROSIS IN PLASMINOGEN-DEFICIENT MICE, The Journal of clinical investigation, 102(10), 1998, pp. 1788-1797
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.