From the Department of Surgery and Pathology, the University of Chicago,
and the Hektoen Institute for Medical Research (A.S.), Chicago, Ill.
Background—MMP-2 plays a key role in
basement membrane degradation and in the migration of proliferating
smooth muscle cells after vascular injury. Because low flow and shear
stress have been related to the localization and progression of intimal
hyperplasia, we hypothesized that flow conditions modulate in vivo
MMP-2 transcription and activity in a model of injury-induced
intimal thickening.
Methods and Results—The right common carotid artery (CCA) was
balloon-injured in 21 New Zealand White male rabbits. Flow was
thereafter preserved (normal flow, n=7), reduced by partial outflow
occlusion (low flow, n=7), or increased by ligation of the left CCA
(high flow, n=7). In 15 other animals (controls without injury), flow
was reduced (n=5), increased (n=5), or preserved (n=5). Mean blood flow
and pressure in the right CCA were measured before and after flow
modulation (day 0) and before the rabbits were killed (day 7). Northern
analysis, gelatin-gel zymography, and fluorometric assays
were performed on day 7 to determine MMP-2 mRNA levels and activity in
relation to flow and intimal thickening. Mean flow was reduced from
21±1 to 7±1 mL/min (P<0.05) by outflow occlusion and
increased to 31±2 mL/min (P<0.05) by ligation of the
contralateral CCA. Blood pressure was not different between the flow
groups. Hemodynamic parameters were similar
for days 0 and 7 after flow modulation. In the injured right CCA, there
was a 186% increase in MMP-2 mRNA with normal flow
(P<0.05), a 366% increase with low flow
(P<0.005), and only a 38% increase with high flow
(P>0.05) compared with the uninjured CCA with normal
flow. In the uninjured CCA, MMP-2 mRNA levels were increased by only
39% and 26% in the low- and high-flow groups, respectively, compared
with normal-flow controls. The zymographic signal and quantitative
fluorescent activity of gelatinase were markedly increased in
both injured and uninjured CCAs subjected to low flow. Intimal
thickening was observed after 1 week only in CCA segments with low flow
and injury.
Conclusions—Hemodynamic forces such as low flow
upregulate injury-induced MMP-2 mRNA and appear to be more important in
regulating MMP-2 activity than injury alone. This may facilitate
migration of the smooth muscle cells and subsequent development of
intimal thickening.
© 1998 American Heart Association, Inc.
Basic Science Reports
Flow Regulation of 72-kD Collagenase IV (MMP-2) After Experimental Arterial Injury
Key Words: hemodynamics • metalloproteinases • hyperplasia
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