Atherosclerosis 150 2000 245 – 253
Atherosclerotic arterial remodeling and the localization of macrophages and matrix metalloproteases 1, 2 and 9 in the human
coronary artery
Gerard Pasterkamp
a,b,
, Arjan H. Schoneveld
a,b
, Dirk Jan Hijnen
a,b
, Dominique P.V. de Kleijn
a,b
, Hans Teepen
c
, A.C. van der Wal
d
, Cornelius Borst
a,b
a
Department of Cardiology, Room G
02
-
523
, Heart Lung Institute, Utrecht Uni6ersity Hospital, Heidelberglaan
100
,
3584
CX Utrecht, The Netherlands
b
The Interuni6ersity Cardiology Institute of the Netherlands, Utrecht, The Netherlands
c
Department of Pathology, Elisabeth Hospital, Tilburg, The Netherlands
d
Cardio6ascular Pathology, Academic Medical Center, Amsterdam, The Netherlands Received 11 January 1999; received in revised form 6 August 1999; accepted 8 September 1999
Abstract
Atherosclerotic luminal narrowing is determined by plaque mass and the mode of geometrical remodeling. Recently, we reported that the type of atherosclerotic remodeling is associated with the presence of histological markers for plaque
vulnerability. Inflammation and matrix degrading proteases MMPs may play a role in both plaque vulnerability and in expansive arterial remodeling. The aim of the present study was to investigate the association between the remodeling mode and the
localization of macrophages and MMPs in coronary atherosclerotic segments. From 36 atherosclerotic coronary arteries, 45 and 51 segments were selected with a vessel area that was \ 10 smaller and larger compared with the adjacent segments, respectively.
No significant difference in staining for macrophages was observed between segments with expansive and constrictive remodeling. More MMP-2 and MMP-9 staining was observed in plaques of expansively remodeled segments compared with constrictively
remodeled segments. In general, MMP-staining was less evident in the adventitial layer compared with the plaque. Zymography revealed more active MMP-2 in expansively remodeled segments compared with constrictively remodeled segments 340 9 319 vs.
199 9 181 adjusted countsmm
2
, respectively, P = 0.019. Zymography did not show differences in inactive MMP-2 or MMP-9 among groups. It might be postulated that MMPs within the plaque play a causal role not only in plaque vulnerability but also
in de novo atherosclerotic remodeling. © 2000 Elsevier Science Ireland Ltd. All rights reserved.
Keywords
:
Atherosclerosis; Remodeling; Matrix metalloproteinases; Artery; Plaque rupture www.elsevier.comlocateatherosclerosis
1. Introduction
Atherosclerotic luminal narrowing is determined by plaque mass and the mode of geometrical remodeling.
Constrictive remodeling accelerates and expansive re- modeling prevents luminal narrowing by plaque forma-
tion [1 – 6]. In the acute phase luminal narrowing may be enhanced by plaque rupture and subsequent throm-
bus formation [7 – 10]. Recently, we reported that in femoral artery segments the type of atherosclerotic
remodeling is associated with the presence of histologi- cal markers for plaque vulnerability: more inflamma-
tory cells but less collagen and smooth muscle cells were observed in the caps and shoulders of cross-sec-
tions that showed expansive enlargement compared with the more stable constrictively remodeled cross-sec-
tions [11]. The concept of this remodeling paradox, that expansive enlargement prevents luminal narrowing on
one hand but may be associated with vulnerable plaques on the other hand, is supported by recently
reported clinical ultrasound studies in which the mode of remodeling was found to be associated with the
patients’ clinical syndrome [12,13].
Corresponding author. Tel.: + 31-30-2507155; fax: + 31-30- 2522693.
E-mail address
:
g.pasterkamphli.azu.nl G. Pasterkamp 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 3 7 1 - 8
Vascular and inflammatory cells can modulate the structure and composition of the extracellular matrix
by producing enzymes involved in its degradation. In vulnerable plaques matrix metalloproteinases MMPs,
that are secreted by macrophages, digest the matrix components within the fibrous cap. In cross-sections of
atherosclerotic arteries revealing extreme expansive re- modeling, like aneurysms, increased MMP activity
within the arterial wall and a higher density of macrophages may be observed within the arterial wall
[14]. Mainly the gelatinases MMP-2 and MMP-9 are highly expressed and more active in enlarged aneurys-
matic arteries.
It remains to be investigated whether the increased prevalence of inflammatory cells in expansively remod-
eled segments compared with constrictively remodeled segments is also evident for the atherosclerotic coronary
artery. In addition, it is unknown if such higher preva- lence of macrophages in enlarged segments is also
associated with an enhanced release of matrix metallo- proteases that are thought to play a pivotal role in both
matrix degradation and plaque destabilization [15 – 18] and atherosclerotic remodeling [14,19].The aim of the
present study was to investigate the association between the
mode of
remodeling and
the presence
of macrophages and MMP-1, MMP-2 and MMP-9 in
coronary atherosclerotic cross-sections. In addition, zy- mography was performed to study the gelatinase activ-
ity in atherosclerotic cross-sections that show expansive and constrictive remodeling.
2. Methods
