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,1 Max Planck Institute, Department of Experimental Cardiology, D-61231 Bad Nauheim, Germany; 2 Department of Anatomy, Hunan Medical University, Changsha 86-731, Hunan, People's Republic of China; and 3 National Institute of Cardiology, Budapest 1125, Hungary
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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We studied the role of the adventitia in adaptive arteriogenesis during the phase of active growth of coronary collateral vessels (CV) induced by chronic occlusion of the left circumflex coronary artery in canine hearts. We used electron microscopy and immunoconfocal (IF) labeling for bFGF, matrix metalloproteinase (MMP)-2, MMP-9, tissue-type plasminogen activator (tPA), its inhibitor (PAI-1), fibronectin (FN), and Ki-67. Proliferation of smooth muscle cells and adventitial fibroblasts was evident. Quantitative IF showed that adventitial MMP-2, MMP-9, and FN were 9.2-, 7.5-, and 8.6-fold, bFGF was 5.1-fold, and PAI-1 was 3.4-fold higher in CV than in normal vessels (NV). The number of fibroblasts was 5-fold elevated in CV, but the elastic fiber content was 25-fold greater in NV than in CV. Perivascular myocyte damage and induction of endothelial nitric oxide synthase in peri-CV capillaries indicate expansion of CV. It was concluded that adventitial activation is associated with the development of CV through cell proliferation, production of growth factors, and induction of extracellular proteolysis thereby contributing to remodeling during adaptive arteriogenesis.
collateral vessel growth; metalloproteinases; extracellular proteolysis; dog
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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CORONARY COLLATERAL VESSEL GROWTH in the dog heart, induced by chronic occlusion of a major coronary artery, results in a 20-50 times increase in diameter (21). The mechanism of collateral vessel growth is only partially understood. Many factors or events have been indicated to make contributions to this process, e.g., increased shear stress, early invasion of monocytes/macrophages, reexpression of fetal proteins, extracellular proteolysis, migration of smooth muscle (SM) cells, and involvement of gap junction proteins (3, 4, 29). The notion that apoptosis of SM cells, fibroblasts, or myocytes creates space for the enlargement of collateral vessels has also been proposed (23). These studies addressed the crucial role of endothelium and of SM cells in the development of coronary collateral vessels. However, the importance of the tunica adventitia in vascular remodeling was largely neglected, although enlargement of collateral vessels without participation of the adventitia seems not conceivable. We hypothesize that the adventitia is activated and might be an important contributor to the development of coronary collaterals.
The development of coronary collateral vessels has been classified into
three phases: early growth (2-3 wk postsurgery), active growth
(4-6 wk postsurgery), and maturation (8-12 wk postsurgery) (4). An early study showed that an acute inflammatory
reaction was present in the adventitia of collateral vessels in the
phase of early growth (2). However, in the phases of
active growth and maturation, inflammatory cells have not been observed
in the adventitia, and fibroblasts are the predominant cells residing in the adventitia. Fibroblasts have been demonstrated to be active participants in vascular remodeling (20, 25, 26). Here, we
studied the question whether typical adventitial cells remain activated
past the stage of acute inflammation and leukocyte invasion. Therefore,
we investigated the expression of matrix metalloproteinase (MMP)-2,
urokinase-type plasminogen activator (uPA), plasminogen activator
inhibitor (PAI)-1, bFGF, and fibronectin in the adventitia of
collateral vessels during the active growth phase. Transmission electron microscopy (TEM) and routine elastica van Gieson and hematoxylin-eosin (H-E) staining were also employed for the
histological study of the adventitia. In addition, antibodies
against desmin, SM 
-actin, and vimentin were used to identify the
phenotypes of SM cells and fibroblasts. We found that the number of
fibroblasts and the expression of MMP-2, MMP-9, PAI-1, bFGF, and
fibronectin were significantly increased in the adventitia, indicating
an active participation of the adventitia in collateral vessel growth.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animal model. The protocol for preparation of this animal model has been previously described (29). Briefly, six adult mongrel dogs weighing 18-20 kg were anesthetized with pentobarbital (138 mM/kg body wt). Under artificial respiration, the thorax was opened, the pericardium was incised, and an Ameroid constrictor was implanted around the circumflex branch of the left coronary artery (LCx). The thorax was closed, and the animals were allowed to recover using analgesics and antibiotics.
The experiments were carried out following the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85-23, Revised 1985).Tissue preparation. At week 6 postsurgery, corresponding to the phase of active growth of collateral vessels, the animals were reanesthetized, the thorax was opened, and the heart was removed. This time point was earlier than that used in previous studies (4). This was caused by a somewhat different quality of the Ameroid used for the constrictor that took up more fluid in a shorter time and led to occlusion of the vessels 4 days earlier. Before this final experimental series was carried out, the different growth stages were determined using neointima formation and proliferative activity as markers.
There were usually two to six collaterals per heart, easily identified on the epicardial surface between the branches of the left anterior coronary artery and the LCx, distant from the site of occlusion (Fig. 1). All midzone samples of the collaterals (22) were removed. Since arterial branches from nonoccluded arteries from the same heart are morphologically not different from true control coronary arteries from control animals, we used size-related coronary arteries from both types of control tissue. A total of 24 collateral and 12 size-matched normal vessels were investigated. The samples for immunohistochemistry and routine histology were immediately frozen in liquid nitrogen, embedded in tissue processing medium (OCT compound), and stored at
80°C till
further use.
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Immunohistochemistry.
Cryosections were cut 5 µm thick and fixed in 4% paraformaldehyde.
After incubation in 0.2% BSA-C (Aurion), the sections were incubated
with primary antibodies (Table 1).
Biotin-SP-conjugated affinipure donkey anti-mouse, anti-rabbit, or
anti-rat IgG (Dianova) secondary antibodies were followed by Cy2- or
Cy3-conjugated streptavidin (Biotrend). The nuclei were stained with
7-aminoactinomycin D (Molecular Probes). The sections were coverslipped
and viewed with a Leica confocal microscope (Leica TCS SP). Further
documentation and image analysis were carried out using a Silicon
Graphics Octane workstation (Silicon Graphics) and three-dimensional
multichannel image processing software (Bitplane).
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Dual immunostaining of myosin, endothelial nitric oxide synthase,
fibronectin, or laminin with vimentin, lectin BS-1, or phalloidin.
The first staining sequence was designed to detect myosin, endothelial
nitric oxide synthase (eNOS), fibronectin, or laminin using the same
protocol as described as above. Afterward, the sections were
washed and incubated with either anti-vimentin antibody (Cy3
conjugated), lectin BS-1, or phalloidin and coverslipped. For
dual immunostaining of vimentin with SM -actin, the sections were
incubated with anti-vimentin antibody (Cy3 conjugated) and anti-SM
-actin (FITC conjugated) and coverslipped.
TEM and histology. Freshly dissected samples were immediately immersion fixed in 2% paraformaldehyde and 1% glutaraldehyde in 0.1 M sodium cacodylate buffer followed by postfixation in 2% osmium tetroxide and embedding in Epon. Semithin sections were stained with Toluidin blue and photographed with a Leica light microscope. Ultrathin sections were stained with uranyl acetate and lead citrate, viewed, and photographically recorded using a Philips CM 10 electron microscope.
H-E and elastica van Gieson stainings were performed on 5-µm-thick cryosections according to routine protocols.Quantitative measurements. The quantification of immunofluorescence intensity of elastic fibers was performed with a Leica TCS SP confocal microscope. One channel with format 512 and appropriate filters was used. A full range of gray values, from black to peak white (0- to 255-pixel intensity levels), was set during the whole process of measurements. With the use of Leica quantitation software, the fluorescence intensity of the adventitia in both normal and growing vessels was measured. The intensity of fluorescence was expressed as arbitrary units (AU) per micrometer squared.
For the quantitation of elastic fibers, images of elastic staining from normal and growing vessels obtained with a Leica DM RB microscope were transferred to a computer equipped with an Adobe Photoshop and NIH Image system. On the basis of the clear outline of the adventitia as evidenced by the red color of collagen, the adventitial layer was separated from the vessel wall and its area was determined using the NIH Image system. Thereafter, the red color was suppressed, and the area of elastic fibers was measured using a threshold of 110 pixels on a scale of 0-255 pixel gray intensity. The area of elastic fiber/adventitial area represents the elastic content and was expressed as a percentage. Quantitation of fibroblasts was performed with the confocal microscope. Vimentin was used as fibroblast marker. To distinguish the adventitia from the media, SM-actin staining was performed. Nuclei were also
stained. The counting was done at ×40 magnification, and only
vimentin-positive cells with nuclear staining were counted and
expressed as the number of cells per 104 µm2.
All data are presented as means ± SE. t-Test was used
to examine the difference between normal vessels and growing vessels.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Histology of the adventitia in normal and actively growing
collateral vessels.
In normal vessels, H-E staining showed that only few
fibroblasts were present in the adventitia (Fig.
2A and Table
2), but a significant increase of the
number of fibroblasts (5 times) was seen in growing collateral vessels
(Fig. 2B and Table 2). This change was also confirmed by
observations from semithin sections (Fig. 2, E and
F).
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Ki-67 and proliferative activity. Inflammatory cells were not observed in the adventitia of actively growing collateral vessels. This is in contrast to the early stage of growth (2). Ki-67 labeling showed numerous proliferating cells, both in the media and in the adventitia. This confirmed the classification of the stage of "active growth" as described earlier (4).
Phenotype and activation of fibroblasts in the adventitia of normal
and actively growing collateral vessels.
To investigate the phenotypic characteristics of fibroblasts in the
adventitia of normal and actively growing collateral vessels, double
immunostaining of vimentin with SM -actin was performed. In normal
vessels, few vimentin-positive cells were observed, but in growing
vessels a large number of these cells was present. However, double
staining revealed that these vimentin-positive cells were SM -actin
negative in either normal or growing vessels (Fig. 3,
A-D), indicating that
they were not myofibroblasts. Activation and mitosis of adventitial
fibroblasts were identified by TEM. In normal vessels, fibroblasts were
quiescent, but they were activated in growing vessels, showing abundant
endoplasmic reticulum and numerous mitochondria (data not shown).
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Expression of MMP-2, MMP-9, tPA, PAI-1, fibronectin, and bFGF in
the adventitia of normal and growing vessels
In normal vessels, bFGF, MMP-2, MMP-9, tPA, and PAI-1 were weakly
stained in the adventitia (data not shown, see Ref. 4). Fibronectin was also moderate (data not shown, see Ref.
4). In growing vessels, bFGF, MMP-2, MMP-9, PAI-1,
and fibronectin were increased 5.1-, 9.2-, 7.5-, 3.4-, and 8.6-fold,
respectively (Fig. 4, A, B, D, and
E, and Fig.
5). tPA was also dramatically increased in the adventitia (Fig. 4C).
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-actin
and BS-1 (an endothelial marker). Vasa vasorum were not found in the
adventitia in collateral vessels (Fig. 4F).
Myosin, connexin43, connexin40, laminin, and eNOS in perivascular
myocardium during active collateral growth.
The expression of myosin, connexin (Cx)43, Cx40, and laminin in the
perivascular myocardium around normal vessels showed the same pattern
as seen in more remote parts of the myocardium (Figs. 6A and
7A); eNOS was weak or negative
in normal myocardium (data not shown). During active collateral growth,
myosin, Cx43, Cx40, and laminin were decreased in the perivascular
myocardium, and damaged zones were observed (Fig. 6,
B-D). Furthermore, eNOS was induced in the capillaries
of perivascular myocardium. Double staining with BS-1 confirmed that
those cells expressing eNOS were endothelial cells (Fig. 6,
E and F). Moreover, in normal circumstances,
there were only a few vimentin-positive cells (most likely capillary
endothelial cells) between cardiomyocytes and moderate fibronectin in
the perivascular myocardium (Fig. 7A). During active
collateral growth, the damaged perivascular myocardium was embedded in
a large number of vimentin-positive cells and fibronectin (Fig. 7,
B and C). Both laminin and actin were
downregulated in these damaged cardiomyocytes (Fig. 7D).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The key finding of the present study may be summarized as follows. During adaptive arteriogenesis in the dog heart, remodeling of the adventitial layer involving activation and proliferation of fibroblasts accompanied by expression of growth factors and an upregulation of the proteolytic system occurs. In addition, perivascular cardiomyocyte damage was observed. Both processes allow for and will contribute to the expansion of growing collateral vessels. These phenomena occur mainly during the phase of active growth, whereas mature vessels are not different from normals. Inflammation is not important for remodeling because the collateral vessels develop far distant from the site of constrictor implantation.
Mitosis of fibroblasts in the adventitia of growing collateral vessels
has been reported earlier by our group (29) and was confirmed in the present study. The fibroblasts were larger, containing abundant rough endoplasmic reticulum and more mitochondria than quiescent cells. These showed the paradigm of activated adventitial fibroblasts. In contrast to those observations from vascular injury and
granulation tissue during wound healing (6, 7, 27), myofibroblasts were not observed in this study. The difference between
our findings and those of others might be due to the different roles
fibroblasts play in different models of arteriogenesis and vascular
injury. This speculative "correlation between structure and
function" is in agreement with a recent report (9). This shows that rat fibroblasts cultured from various organs exhibit differences in SM -actin expression and the cytoskeleton pattern and
suggests phenotypic differences probably associated with different functional activities such as metabolic activation and protein synthesis. In addition, expression of SM -actin in fibroblasts is
transient. Therefore, the possibility that SM -actin might be
present at some time point in adventitial fibroblasts in the early
stage of growth could not be excluded in this study.
The mechanism for activation of fibroblasts is only partly understood. It has been suggested that phenotypic modulation of fibroblasts is due to microenvironmental changes induced by injury (5, 27). In our model, acute vascular lesions were also present in the early stage of collateral growth, but in the active phase of growth inflammatory cells were absent (2). Recently, one study (13) showed that mechanical tension was crucial for myofibroblast modulation in granulation tissue. We assume that blood pressure and shear stress may be the important inducers of activation of fibroblasts.
Role of adventitial extracellular proteolysis during arteriogenesis. Recently, we have shown that extracellular proteolysis is associated with the degradation of the elastic lamina and migration of medial SM cells during arteriogenesis in the dog heart (4). The present study adds to the knowledge that adventitial extracellular proteolysis is also activated during arteriogenesis. In normal small arterioles, the adventitial inner part contains elastic fibers. It has been suggested that circumferential arterial wall stress may be borne primarily by elastin (8). The high expression of MMP-2 and MMP-9 in the adventitia suggests an active role in degradation of elastin and other extracellular matrix components to facilitate enlargement of growing collateral vessels. That MMPs are present in activated forms in growing collateral vessels has recently been shown by our group (4).
The increased expression of tPA may imply its participation in adventitial extracellular proteolysis. Evidence from experiments of injured rat arteries and development of atherosclerotic and restenotic lesions have shown the positive correlation between the expression of plasminogen activators tPA and uPA and the migration of SM cells into the intima (16, 19). In addition, plasmin may activate MMPs (17) to augment adventitial extracellular proteolysis. The migration of fibroblasts in the present study was in contrast to that seen in angioplasty or vein graft models, where fibroblasts moved toward the intima (20). Probably this has resulted from the high expression of inhibitors of proteinases, such as TIMP-1 and PAI-1, in the SM cells of the media (4), which formed a barrier to inhibit the movement of fibroblasts into the intima, or due to the different models used (15). Fibronectin, an important extracellular protein, is crucial for fibroblast transmigration (11). The presence of large amounts of fibronectin in the adventitia provides further evidence for the notion of migration of fibroblasts. This finding is in agreement with a previous report (1). The importance of a balance between extracellular proteolysis and antiproteolysis has been emphasized in several reports (4, 10, 12). Because of the absence of TIMP-1 and TIMP-2 in the adventitia (4), it was speculated that an increased expression of PAI-1 might play an important role in the control of adventitial extracellular proteolysis by a dual-negative feedback effect of both, downregulating plasmin-mediated degradation and downregulating MMP activation. Further experiments using different TIMP antibodies are needed to clarify this issue. Figure 8 illustrates schematically the sequence of events in arteriogenesis, with special emphasis on the role of the adventitia.
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Role of bFGF. The finding in this study of induced expression of bFGF in the adventitia and other layers of the collateral vessel wall further supports the notion of an angiogenic effect of bFGF, as reported by another group (28). Increased expression of bFGF has been also found in the entire wall of collateral vessels at the phase of early growth, whereas MMP-2 and MMP-9 were only present in the thin intima and media but not in the adventitia (4). This time difference between the expression of bFGF and MMPs may suggest that bFGF regulates the production of MMPs, which has been demonstrated by in vitro gene transfection studies (18). In addition, bFGF was found to induce PAI-1 biosynthesis in capillary endothelial cells (24). Taken together, the increased expression of bFGF is likely to be necessary for cell proliferation, degradation of extracellular matrix, and cell migration during the development of collateral vessels.
Perivascular myocardial damage in intramural growing collateral vessels. As the collateral vessel develops, the space around it becomes a limiting factor. However, when the growth process continues, perivascular myocardial damage caused by expansion of the growing collateral vessel is predictable. In this study, a damage zone of myocardium around the growing collateral vessels was observed, which showed a decreased expression of gap junction proteins (Cx43 and Cx40) as well as myosin, actin, and laminin. Myocytes smaller than normal were embedded in large amounts of fibronectin, and there was an accumulation of vimentin-rich cells. The damage of the neighboring myocytes may be induced by hypoxia because of the characteristic encasement of cardiomyocytes by fibronectin or collagens. The increased expression of eNOS in the capillaries in this region may serve as additional evidence of hypoxia, which was reported to induce expression of eNOS in coronary microvessels (14). To our knowledge, this is the first report that arteriogenesis in individual vessels could exert a negative effect on the surrounding myocardial cells. This raises the question as to what extent the function of the heart may be influenced by this kind of damage and how arteriogenesis can be controlled. Further work is required to solve this problem.
In conclusion, these data for the first time show that remodeling of the adventitia is associated with the development of collateral vessels in the dog heart. The findings of high expression of bFGF, active extracellular proteolysis, and cell proliferation point to the importance of these mechanisms for enlargement of collateral vessels and may serve as a springboard for future mechanistic studies.| |
ACKNOWLEDGEMENTS |
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The authors thank Gunther Schuster and Gerhard Stämmler for help with computer assistance and Annemarie Möbs for photographic work.
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FOOTNOTES |
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Deceased 19 November, 2001.
Address for reprint requests and other correspondence: J. Schaper, Max-Planck Institute, Dept. of Experimental Cardiology, Benekestrasse 2, D-61231 Bad Nauheim, Germany (j.schaper{at}kerckhoff.mpg.de).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published August 29, 2002;10.1152/ajpheart.00478.2002
Received 7 June 2002; accepted in final form 23 August 2002.
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REFERENCES |
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TOP
ABSTRACT
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MATERIALS AND METHODS
RESULTS
DISCUSSION
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