Publication: Antisense oligonucleotides to stromelysin mRNA inhibit injury-induced proliferation of arterial smooth muscle cells
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Date
1999
Authors
Lovdahl, C. ; Thyberg, J. ; Cercek, B. ; Blomgren, K. ; Dimayuga, P. ; Kallin, B. ; Hultghrdh-Nilsson, A.
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Publisher
Murcia : F. Hernández
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DOI
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info:eu-repo/semantics/article
Description
Abstract
Smooth muscle cell migration and
proliferation are important events in the formation of
intimal lesions associated with atherosclerosis and
restenosis following balloon angioplasty. To make this
possible, the smooth muscle cell has to change from a
contractile to an activated repair cell with capacity to
synthesize DNA and extracellular matrix components.
There is now considerable evidence that the extracellular
matrix has important functions in modulating the
phenotypic properties of smooth muscle cells, but less is
known about the role of the matrix metalloproteinases.
The present study investigates the role of stromelysin in
the modulation of rat aortic smooth muscle cell
morphology and function following mechanical injury in
vitro and in vivo. Antisense mRNA oligonucleotides
were used to investigate the role of stromelysin
expression in injury-induced phenotypic modulation and
the subsequent migration and proliferation of vascular
smooth muscle cells. Cultured rat aortic smooth muscle
cells and balloon-injured rat carotid arteries were used as
experimental models. Light- and electron microscopy
were used to follow changes in smooth muscle cell
phenotype and lesion formation and incorporation of 3 ~ -
thymidine to detect DNA synthesis. Injury-induced
DNA synthesis and migration in vitro were inhibited by
72% and 36%, respectively, by adding stromelysin
antisense oligonucleotides to the medium prior to injury.
In primary cultures, 67% of the smooth muscle cells
treated with stromelysin antisense were retained in a
contractile phenotype as judged by analysis of cell fine
structure, compared to 15% untreated cells and 40% in
cells treated with mismatched oligonucleotides.
Examination of the carotid arteries one week after
balloon injury likewise demonstrated a larger fraction of
contractile cells in the inner parts of the media in vessels
treated with antisense oligonucleotides compared to
Offprint requests to: Anna HultgArdh-Nilsson, Lund University,
Departrnent of Cell and Molecular Biology, Division of Connective
Tissue Biology, P. O. Box 94, S-221 00 Lund, Sweden. Fax: t46-46-211
3417. e-rnail: Anna.Hultgardh@rnedkern.lu.se
those treated with mismatched oligonucleotides. The
neointima was also distinctly thinner in antisense-treated
than in mismatched-treated and control arteries at this
time. These findings indicate that stromelysin mRNA
antisense oligonucleotides inhibited phenotypic
modulation of rat arterial smooth muscle cells and so
caused a decrease in migration and proliferation and
neointima formation in response to vessel wall injury.
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