© 1999 American Heart Association, Inc.
Original Contribution |
Plasminogen Is Not Required for Neointima Formation in a Mouse Model of Vein Graft Stenosis
From the Cardiovascular Biology Laboratory (C.S., A.P., D.Z., H.W., G.L.R., M.-E.L., E.H., N.E.S.S.), Harvard School of Public Health, Boston, Mass; Department of Medicine (N.E.S.S., G.L.R., M.-E.L., E.H.), Harvard Medical School, Boston, Mass; Cardiovascular Division (N.E.S.S., M.E.-L.), Brigham and Women's Hospital, Boston, Mass; Cardiac Unit (G.L.R.), Massachusetts General Hospital, Boston, Mass; and the Center for Transgene Technology and Gene Therapy (P.C.), Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium.
Correspondence to Nicholas E.S. Sibinga, MD, Cardiovascular Biology Laboratory, Harvard School of Public Health, 677 Huntington Ave, Boston, MA 02115. E-mail sibinga{at}cvlab.harvard.edu
Abstract—Recent studies of
mice that lack plasminogen have identified a critical role
for this zymogen in arterial remodeling. To permit the use
of these (and other) genetically modified mice in the analysis
of venous injury, we developed a model in which a patch cut from the
external jugular vein of a mouse is grafted to repair a surgically
created defect in its carotid artery. In wild-type mice, the venous
graft showed initial endothelial denudation and
formation of a neointima that progressively and
reproducibly expanded in a manner analogous to human vein graft
disease, albeit at an accelerated pace. This neointima
occupied 37±4.6% of the vessel lumen at day 7 and 66±5.7% at day
20. The proliferative index of neointimal cells assessed by
proliferating cell nuclear antigen staining was 50.6±3.6% at day 7
and 15.2±2.0% at day 20. CD45-positive leukocytes and
-actin–positive smooth muscle cells accounted for 9.5±1.0% and
9.9±1.1% of intimal area at day 7, respectively, with the latter
increasing to 40.9±2.6% at day 20. Collagen accounted for 6.8±0.7%
of intimal area at day 7 and 20.7±1.8% at day 20. Surprisingly, even
though arterial neointima formation due to
electrostatic and immune-mediated injury is impaired in
plasminogen –/– mice, in our study vein graft
neointima formation in these mice was not significantly
different from that in controls (70.9±6.4 versus 65.6±4.4% luminal
occlusion, P=NS). Thus, plasmin proteolysis, although
critical in extracellular matrix degradation and cellular migration
after arterial injury, does not appear to be so important
in vein graft neointima formation, perhaps because of the
relative lack of structural barriers to cellular migration in the
normal vein wall. This novel model of vein graft injury should be
useful for further studies of differences in the response to injury of
arterial and venous tissues.
Key Words: bypass surgery • coronary disease • intimal hyperplasia • arteriosclerosis • gene knockout
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