Pc. Lee et al., Endothelial nitric oxide synthase protects aortic allografts from the development of transplant arteriosclerosis, TRANSPLANT, 69(6), 2000, pp. 1186-1192
Background. Inducible nitric oxide synthase (iNOS) is up-regulated in rejec
ting allografts and is protective against allograft arteriosclerosis; it su
ppresses neointimal smooth muscle cell accumulation and inhibits adhesion o
f platelets and leukocytes to the endothelium. However, the functional impo
rtance of endothelial NOS (eNOS) in the rejecting allografts remains unclea
r.
Methods. We examined the effects of selective eNOS deficiency in aortic all
ografts in a murine chronic rejection model using grafts from eNOS knockout
(KO) mice (C57BL/6 background; H2(b)) and normal C3H (H2(K)) as recipients
. Grafts from wild-type C57BL/6 mice served as controls. Grafts from iNOS K
O mice served as a second group of controls where the contribution from iNO
S was eliminated but eNOS was preserved. Aortic grafts were harvested and a
nalyzed at days 10-14, 18-22, and 26-30 after transplantation.
Results. Endothelial NOS-deficient grafts showed significantly increased in
tima/media ratios at days 26-30 compared to controls. Immunostaining demons
trated that in eNOS KO grafts, eNOS was not detectable whereas iNOS was exp
ressed prominently in infiltrating recipient mononuclear cells. In control
grafts, eNOS expression was preserved in the endothelium even by day 30, an
d associated with a decrease in intimal thickening. We further demonstrated
that early overexpression of iNOS by ex vivo gene transfer completely prev
ented the development of arteriosclerosis associated with eNOS deficiency.
Conclusions. We found that eNOS plays a protective role in allografts, and
that in eNOS deficient allografts, early overexpression of iNOS is capable
of preventing the development of allograft arteriosclerosis. In allo grafts
with dysfunctional vascular endothelium and impaired eNOS activity as a re
sult of ischemia or native arteriosclerotic disease, iNOS gene therapy may
serve to improve their long-term survival and function.