Atherosclerosis 152 2000 287 – 298
Differential expression of proteoglycans biglycan and decorin during neointima formation after stent implantation in normal and
atherosclerotic rabbit aortas
Tomoyuki Yamakawa
a,
, Hong-zhi Bai
a
, Junichi Masuda
b
, Yoshiki Sawa
a
, Ryota Shirakura
c
, Jun Ogata
d
, Hikaru Matsuda
a
a
Department of Surgery, Course of Inter6entional Medicine E
1
, Osaka Uni6ersity Medical School,
2
-
2
Yamada-oka, Suita, Osaka
565
, Japan
b
Department of Laboratory Medicine, Shimane Medical Uni6ersity, Izumo, Shimane
693
, Japan
c
Di6ision of Organ Transplantation Biomedical Research Center, Osaka Uni6ersity Medical School,
2
-
2
Yamada-oka, Suita, Osaka
565
, Japan
d
National Cardio6ascular Center Research Institute, Suita, Osaka
565
, Japan Received 10 June 1999; received in revised form 25 October 1999; accepted 5 November 1999
Abstract
Proteoglycans decorin and biglycan, which bind to TGF-b, are thought to participate in regulation of extracellular matrix accumulation in arterial intimal hyperplasia. To investigate the correlation of these proteoglycans with the cellular localization and
phenotypic modulation of smooth muscle cells SMCs, we analyzed the spatial and chronological distribution of these proteoglycans and two cytokines, TGF-b and IL-1b, in the process of neointima formation after stent implantation in the aortas
of rabbits fed a high-cholesterol diet atherosclerotic group or a regular diet control group. We implanted metallic stents in the rabbit aortas and harvested the aortas 4 – 56 days later for immunohistochemical and mRNA in situ hybridization analyses. In the
control group, TGF-b and biglycan expression was in correspondence with the chronology and localization of embryonic SMCs. In the atherosclerotic group, TGF-b and biglycan expression was sustained throughout the experimental period, which was in
accord with the prolonged expression of embryonic SMCs. Decorin, which did not occur in neointima in the control group, appeared in the atherosclerotic aortas in the confined area of vascular SMCs surrounding the macrophages around the stent wire.
These results indicate that biglycan and decorin kinetics during neointima formation after arterial injury are distinct, despite their similar construction; biglycan synthesis correlates with embryonic SMCs. © 2000 Elsevier Science Ireland Ltd. All rights reserved.
Keywords
:
Stent; Restenosis; Extracellular matrix; Proteoglycan; Imunohistochemistry; In situ hybridization www.elsevier.comlocateatherosclerosis
1. Introduction
Several clinical studies have demonstrated that intra- coronary stent implantation in conjunction with percu-
taneous transluminal coronary angioplasty PTCA has an advantage over PTCA alone in maintaining long-
term patency, and may thus reduce the incidence of restenosis after angioplasty [1 – 3]. Such a reduction in
restenosis is thought to be due to the larger acute gain obtained by stent implantation. However, the late loss
of diameter due to intimal hyperplasia is even greater after stenting than after PTCA. Thus, restenosis after
stenting remains an unsolved problem. We recently analyzed the spatial and chronological distribution of
cellular components during neointima formation after stent implantation in normal rabbit aortas [4] and we
observed that the compression injury due to stent im- plantation led to neointima formation through tran-
sient proliferation and phenotypic modulation of smooth muscle cells SMCs. The targets of angio-
plasty, however, are highly atherosclerotic vessels, and the mechanism of the response to vascular stent injury
in such vessels is not yet well examined.
Corresponding author. Tel.: + 81-6-68793154, fax: + 81-6- 68793159.
E-mail address
:
yamakawashirasagi-hp.or.jp T. Yamakawa. 0021-915000 - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 0 2 1 - 9 1 5 0 9 9 0 0 4 7 5 - X
Accumulation of extracellular matrix ECM is an- other major event in the intimal hyperplasia following
arterial injury, as are the migration and proliferation of SMCs [5]. Atherosclerotic lesions also contain a great
amount of various ECM components. Recent studies revealed that ECM not only maintains the structural
integrity of the tissues, but also interacts with cellular components and regulates their functions [6,7].
Proteoglycans are a family of noncollagenous glyco- proteins constituting ECM. The functions of proteogly-
cans are varied, and some of them are known to interact with particular cytokines [8]. Recent studies on
fibroproliferative lesions such as in liver fibrosis, [9] pulmonary fibrosis [10] and atherosclerosis [11] have
focused on two kinds of leucine-rich small proteogly- cans, biglycan and decorin, which can bind to trans-
forming growth factor-beta TGF-b, the most potent inducer of ECM synthesis [12,13]. Decorin, in particu-
lar, neutralizes the effect of TGF-b activities in vitro and in vivo [14,15]. These proteoglycans may therefore
have a role in the modulation of ECM synthesis and accumulation.
Atherosclerotic lesions also contain a large number of macrophages secreting various kinds of cytokines
such as TGF-b and interleukin-1 IL-1. Recently IL-1 was reported to enhance the production of decorin in
arterial SMCs in vitro, [16] suggesting the dynamic interactions of macrophages with ECM formation in
atherosclerotic lesions.
The above findings prompted us to examine the spatial and chronological distribution of the expressions
of decorin and biglycan in the association of TGF-b and IL-1 expression in normal and atherosclerotic rab-
bit aortas after vascular stent implantation in order to clarify the ECM kinetics in the process of neointima
formation.
2. Materials and methods
