Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Circulation. 1996;93:1141-1147

This Article
Right arrow Abstract Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Riessen, R.
Right arrow Articles by Isner, J. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Riessen, R.
Right arrow Articles by Isner, J. M.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH

(Circulation. 1996;93:1141-1147.)
© 1996 American Heart Association, Inc.

Articles

Distribution of Hyaluronan During Extracellular Matrix Remodeling in Human Restenotic Arteries and Balloon-Injured Rat Carotid Arteries

Reimer Riessen, MD; Thomas N. Wight, PhD; Christopher Pastore, BA; Courtney Henley, BA; Jeffrey M. Isner, MD

From the Departments of Medicine (Cardiology) and Biomedical Research, St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass, and the Department of Pathology, School of Medicine, University of Washington, Seattle (T.N.W.).

Correspondence to Jeffrey M. Isner, MD, St Elizabeth's Medical Center, 736 Cambridge St, Boston, MA 02135. E-mail jisner@opal.tufts.edu.


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Background The glycosaminoglycan hyaluronan (HA) is present in developing tissues and healing wounds and forms a loose, hydrated extracellular matrix (ECM) that promotes processes such as cell migration. To investigate the potential contribution of HA to the pathogenesis of restenosis, we studied (1) human lesions obtained by directional atherectomy and (2) experimentally induced neointima formation in balloon-injured rat carotid arteries.

Methods and Results A biotinylated proteoglycan fragment that binds specifically to HA was used to stain atherectomy specimens from 29 human restenotic lesions (mean restenosis interval, 6.0±4.4 months) and 8 human primary lesions. The loose myxoid ECM typical of human restenotic arteries demonstrated intense, diffuse staining for HA. The intensity was inversely related to the density of immunostaining for collagen types I and III and was lowest in hypocellular primary atherosclerotic plaque. Among 24 rat carotid arteries retrieved 3, 7, 14, 28, 42, or 56 days after balloon injury and immunostained as well for proliferating cell nuclear antigen, staining for HA in the neointima reached a maximum 7 days after balloon injury and was associated with the presence of proliferating, PCNA-positive smooth muscle cells.

Conclusions Hyaluronan is a characteristic constituent of the loose myxoid ECM in human restenotic arteries and of the neointima in experimentally injured arteries. The presence of hyaluronan may be a marker for an initial phase of the extracellular matrix remodeling that occurs during the development of a fibroproliferative lesion and could facilitate biological processes such as cell migration.


Key Words: remodeling • collagen • arteriosclerosis • restenosis • hyaluronic acid


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
The vascular injury induced by balloon angioplasty or other methods for percutaneous revascularization initiates a healing response that can result in renarrowing of a large percentage of treated vessel segments.1 2 Studies analyzing the morphology of these restenotic arteries, retrieved at autopsy or by directional atherectomy, have frequently reported finding foci of FPT in restenotic specimens.3 4 5 6 7 8 One of the typical characteristics of FPT is a loose, myxoid-appearing ECM that surrounds stellate vascular SMCs.3 4 8 Production and deposition of ECM contribute by at least two important means to the pathogenesis of restenosis9 10 : not only does ECM constitute most of the volume of FPT foci, but a specialized ECM also facilitates cell migration and proliferation, believed to be key elements in restenotic lesion development.11 We recently showed that FPT can be distinguished from tissue taken from primary plaques by a different distribution of collagen types I and III and the associated proteoglycans biglycan and decorin.8 To further identify the nature of the ECM in FPT and determine which ECM molecules are involved in the formation of the myxoid tissue, we examined tissues obtained from human restenotic and primary atherosclerotic arteries as well as experimentally injured rat carotid arteries for the presence of HA.

HA is a chainlike glycosaminoglycan that consists of up to 50 000 repeats of the simple disaccharide glucoronic acid/N-acetylglucosamine. It is known from developmental studies that HA is a primary component of the ECM in many tissues during early stages of development before terminal tissue differentiation.12 13 Tissues enriched in HA undergo expansion due to the ability of HA to bind large amounts of water. This expansion creates a loose, hydrated ECM that facilitates cell migration and proliferation, two events critical to arterial development and disease.14 Increased HA production is characteristic of tissue remodeling, since HA is also produced during the early stages of cutaneous wound healing.15 16 17

In this study, atherectomy specimens from human restenotic and primary atherosclerotic lesions were stained with a specific probe for HA, and the presence of HA was related to other ECM components and markers for specific cell types. Additionally, we investigated the time course of HA deposition in the balloon-injured rat carotid artery model.


*    Methods
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Patients
Tissue specimens were retrieved by directional atherectomy from 47 patients with coronary and peripheral artery disease as previously described.18 19 Twenty-nine specimens (21 coronary, 8 peripheral) were retrieved from restenotic lesions between 5 days and 17 months (mean±SD, 6.0±4.4 months) after previous balloon angioplasty. Eight specimens (6 coronary and 2 peripheral) were obtained from sites not previously treated by percutaneous revascularization and were designated primary lesions. Control tissues from 5 internal mammary arteries were retrieved during coronary artery bypass surgery. Tissues were fixed in either 4% paraformaldehyde or methanol.

Balloon Catheter Injury Model
Endothelial denudation was performed in the left common carotid artery of male Sprague-Dawley rats (Charles River Breeding Laboratories, Kingston, Mass) weighing 300 to 400 g. The animals were studied in accordance with guidelines established by the American Heart Association for animal research and with the approval of St Elizabeth's Institutional Animal Care and Use Committee. After anesthesia with sodium nembutal 0.05 mg/g body wt IP, a 2F Fogarty balloon catheter (American Edwards Laboratories) was introduced into the left external carotid artery and passed three times through the common carotid artery as described previously.20 Rats (n=24) were killed after 3, 7, 14, 28, 42, or 56 days. After excision, ballooned and contralateral control arteries were washed in PBS, immersion-fixed in methanol overnight, and embedded in paraffin.

Hyaluronan Staining
Hyaluronan staining can be performed by use of the specific hyaluronan-binding properties of certain proteoglycan domains.21 22 We used b-PG prepared according to the method of Green et al23 (gift of Dr C.B. Underhill, Georgetown University, Washington, DC). After deparaffinization and rehydration or after completion of the first immunostaining (see below), b-PG (4 µg/mL in 10% goat serum/PBS) was applied for 1 hour at room temperature. Sections were then washed five times for 1 minute in PBS. This was followed by the addition of alkaline phosphatase–conjugated streptavidin (Biogenex) for 20 minutes, washing in Tris-buffered saline, and application of the chromogen fast red (Biogenex) for 10 to 20 minutes. To block potential endogenous alkaline phosphatase activity, levamisole (1 mmol/L, Sigma Chemical Co) was added to the chromogen. Sections were lightly counterstained with hematoxylin. No difference in staining was seen between tissues fixed in methanol or paraformaldehyde. To control for nonspecific staining, two different procedures were used. First, b-PG was mixed before application to the section with 0.1 mg/mL hyaluronic acid (Sigma) to preabsorb the b-PG probe. Second, b-PG was mixed with Streptomyces hyaluronidase (0.4 vial/mL, Sigma) to destroy hyaluronan in the tissue section enzymatically. Both procedures completely abolished staining.

Immunostaining
Immunostaining in human sections was performed with an affinity-purified polyclonal rabbit antibody against human collagen I (Biodesign)24 and monoclonal antibodies against human collagen type III (clone HWD 1.1, Biogenex),25 muscle actin (HHF 35, Enzo),26 and macrophages (HAM 56, Enzo)27 as described previously8 with a biotin-streptavidin-peroxidase kit (Biogenex) and diaminobenzidine as the chromogen.

Because previous investigations28 29 have documented that formalin fixation attenuates immunostaining for PCNA, only specimens fixed in methanol were used for double staining with anti-PCNA antibodies.28 30 Staining was performed according to a protocol described by Pickering et al28 with the following modifications: the monoclonal mouse antibody against PCNA (clone PC 10, Signet)28 31 32 was applied at a dilution of 1:50 (IgG concentration, 0.5 µg/mL) in PBS/10% horse serum and incubated for 1 hour at 37°C. For staining of rat tissue sections, 10% rat serum was added to the secondary antibody solution to preabsorb a slight cross-reactivity of the anti-mouse IgG antibody (Signet) to rat IgG. Negative controls were incubated with purified mouse IgG (0.5 µg/mL). Rabbit ileum or colon was used as positive control. Finally, sections of all tissues were stained with an elastic tissue trichrome stain.


*    Results
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
*Results
down arrowDiscussion
down arrowReferences
 
Human Arteries
Cross sections of human internal mammary arteries retrieved during bypass surgery showed very intense staining for HA in the adventitia, patchy HA deposition in the media, and strong staining in the intima (Fig 1ADown).



View larger version (145K):
[in this window]
[in a new window]
  		Figure 1. A, Cross section of a human internal mammary artery demonstrating moderate intimal thickening. Staining for HA in the intima is most intense in the cell layers closest to the lumen. The media shows patchy staining and the adventitia strong, homogeneous staining for HA. Bar=2 µm. B, High-power view of FPT in a coronary restenotic lesion retrieved 3 months after angioplasty, double-stained for HA (red chromogen) and muscle actin (brown chromogen). SMCs are surrounded by an HA-rich ECM. Bar=2 µm.

FPT characterized by stellate SMCs embedded in a loose ECM was found in 8 of 21 coronary restenotic specimens (38%) and 6 of 8 peripheral restenotic tissues (75%). FPT was present in none of the 6 coronary primary lesions and in 1 of 2 primary peripheral specimens. In all of the 15 specimens containing FPT, a large portion of the loose, myxoid ECM exhibited intense, diffuse staining for HA around stellate SMCs (Fig 1BUp). The HA staining patterns observed in coronary versus peripheral lesions also showed no consistent differences. We were unable to demonstrate a correlation between the interval after angioplasty and the intensity of HA staining. Immunostaining of serial sections with antibodies for collagen types I and III revealed, in areas with FPT, an inverse relation between staining intensity for HA and these collagen types: HA was strongest in areas demonstrating weak, patchy staining for collagen types I and III, whereas HA staining was markedly reduced in areas exhibiting a dense array of collagen fibers (Figs 2Down and 3Down). Accordingly, staining for HA was reduced in collagen-rich fibrous plaque typical of primary atherosclerosis, with the exception that focal deposits of HA were observed in tissue clefts that harbored SMCs (Fig 2Down) or macrophages (Fig 3Down). In fact, of the 20 specimens in which either double-staining or staining of serial sections for HA and macrophages was performed, 14 showed intense HA staining around macrophage foci in atherosclerotic plaque. Not all macrophages dispersed in the plaques, however, were associated with an HA-rich ECM.



View larger version (126K):
[in this window]
[in a new window]
  		Figure 2. A, Low magnification of the elastic tissue trichrome staining of a peripheral restenotic lesion retrieved 7 months after angioplasty. A large area of FPT is clearly separated from an area with dense fibrous tissue typical for primary atherosclerotic plaque. Bar=10 µm. B, In this adjacent section, the FPT again shows a patchy staining for collagen type III, whereas collagen staining in areas of primary plaque is much more homogeneous. C, In contrast, staining for HA appears inversely related to that for collagen, with dense, homogeneous staining for HA in the restenotic regions and only focal deposits of HA in areas of primary plaque. D, High-power view of the restenotic portion of previous specimen, double-stained for HA and PCNA. The numerous PCNA-positive SMCs in this tissue are surrounded by an HA-rich matrix. Bar=10 µm.



View larger version (16K):
[in this window]
[in a new window]
  		Figure 3. A, Elastic tissue trichrome stain of a 6-month-old peripheral restenotic lesion, characterized by three different tissue layers: right, a pocket of myxoid FPT; middle, a dense layer of SMCs; and left, primary plaque (P) with extensive macrophage infiltration (confirmed by immunostaining with the macrophage marker HAM56, not shown) and some neovessel formation. Bar=10 µm. B, Collagen type III immunostaining shows very little collagen deposition in the myxoid tissue and in the macrophage-rich areas. In contrast, strong collagen immunostaining is found in the SMC layer in the middle and in the hypocellular portions of the primary plaque. C, Staining for HA again demonstrates an inverse pattern with very strong staining in the myxoid area and the macrophage-rich portion and very little staining in the collagen-rich SMC layer and in the hypocellular primary plaque. D, A higher magnification of the same section, double-stained for HA and PCNA. In this section, PCNA-positive SMCs are found primarily in a cell layer that contains little HA. Bar=2 µm.

PCNA-positive SMCs were observed in HA-rich areas (Fig 2Up), although foci of HA were not a prerequisite for such proliferative activity (Fig 3Up).

Balloon-Injured Rat Carotid Arteries
Normal rat carotid arteries showed strong staining for HA in the adventitia, whereas intima and media contained little HA (Fig 4ADown). Three days after balloon injury, before a neointima had formed, PCNA-positive SMCs were found in the media, surrounded by an HA-rich ECM (Fig 4BDown). This early phase after arterial injury is characterized by migration of SMCs.20 33 SMCs originating from the media subsequently cross the internal elastic membrane and form a neointima.20 A neointima consisting of a large portion of proliferating SMCs was present 7 days after balloon injury (Fig 4CDown). At this point, staining for HA in balloon-injured arteries had already reached its maximum and was observed throughout the entire neointima. Two weeks after balloon injury, the neointima had gained in thickness, and PCNA-positive cells were found mainly in the cell layers adjacent to the lumen (Fig 4DDown). The ECM surrounding the PCNA-positive cells also showed the highest intensity of HA staining. In contrast, staining for HA had been nearly extinguished in the media and the deeper layers of the intima. At later time points, up to 8 weeks after injury, cellular proliferation returned to very low levels and HA staining continued to diminish (Fig 4EDown).




View larger version (220K):
[in this window]
[in a new window]
  		Figure 4. A, Staining of a normal rat carotid artery demonstrates the presence of HA (red chromogen) in the connective tissue of the adventitia, whereas media and intima contain only very little HA (arrow indicates the location of the internal elastic membrane). Bar=2 µm. B, Three days after balloon injury, positive (brown) nuclear staining for PCNA is present in the media. The media also shows staining for HA. C, After 1 week, a neointima, consisting of PCNA-positive SMCs, has formed. This neointima stains strongly for HA. D, After 2 weeks, the proliferation rate is decreasing and PCNA-positive cells are found predominantly in cell layers adjacent to the lumen. These areas also demonstrate the highest intensity of HA staining. E, In arteries retrieved at later times, here shown after 8 weeks, neointimal staining for PCNA and HA has mostly disappeared.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
In this study, we demonstrate that HA is a characteristic component of the loose myxoid FPT of human restenotic lesions.5 6 7 8 HA accumulated in areas that contained little collagen types I and III; conversely, HA was reduced in collagen-rich areas of the lesions. The pattern of HA distribution in restenotic lesions contrasts with the distribution pattern of biglycan and decorin, the proteoglycans that are enriched in the collagen-rich zones of restenotic lesions.8

Studies investigating biological processes such as morphogenesis, wound healing, and tumorigenesis in various organ systems have suggested that the temporal presence of HA in the ECM is a marker for an early stage of ECM remodeling. At later stages, HA is gradually replaced by a more "mature" ECM, consisting of collagens, other fibrous proteins, and proteoglycans12 14 : for example, the early phase of many developing systems involves invasion of cells into highly hydrated, HA-rich matrices. Collagen synthesis at this point is minimal. At later stages, HA synthesis is downregulated, HA is degraded, collagen production increases, and cells begin to differentiate. In adult organisms, a similar sequence of ECM remodeling can be observed in tumorigenesis14 and wound healing.34 35 In wound healing, an early event is the formation of a temporary ECM consisting of HA, fibronectin, and fibrin, followed by the invasion of macrophages, fibroblasts, and new blood vessels. During the next phase, HA and fibrin are degraded and the synthesis of fibrous proteins and associated proteoglycans occurs in association with wound contraction.

Studies using biochemical methods to measure glycosaminoglycans in atherosclerotic human arteries have also found decreased HA concentrations in advanced atherosclerotic lesions,36 37 whereas collagen content is increased.38 In a recent immunohistochemical study, the presence of HA and of the HA-binding protein hyaluronectin was demonstrated in diffuse intimal thickening typical of early atherosclerotic lesions.39 In advanced atherosclerotic lesions, HA and hyaluronectin staining were most intense around extracellular microcrystalline calcific deposits. In the present series of atherectomy specimens, microcrystalline calcific deposits were found in only 2 of 37 tissues. These calcific deposits were indeed surrounded by an HA-rich ECM.

The hypothesis that HA deposition is an early event in the course of ECM remodeling after vascular injury is supported by our findings in the rat carotid injury model. As early as 3 days after injury, increased HA staining was detected in the media. At this point, medial SMCs begin to proliferate and migrate through the internal elastic membrane to form a neointima.20 40 One week after injury, a time when proliferative activity in the neointima reaches its peak,20 HA filled the ECM. At 2 weeks, staining for HA decreased in parallel with diminishing proliferative activity, remaining limited to cell layers near the luminal surface, the site of most residual proliferative activity.41 At later times, HA staining in the neointima was further reduced or, in many cases, not even detectable. A similar observation has been made in a double-injury model of restenosis involving cholesterol-fed rabbits, in which HA accumulation appears in the neointima of the second lesion during the first 7 to 14 days after the second injury (G. Skinner, T.N. Wight, E.W. Raines, and R. Ross, unpublished observations). Studies of single balloon-injured rabbit arteries have also disclosed biochemical evidence of early increases in HA.42

Synthesis of HA in human SMCs (C. Evanko and T.N. Wight, unpublished observation) and other cell types43 44 is stimulated by transforming growth factor-ß1 and platelet-derived growth factor, two growth factors central not only to elaboration of ECM but also to cell migration.45 Previous studies suggest that HA influences cell migration by a variety of mechanisms.12 46 For example, HA may influence cell migration by (1) reducing cell attachment to adhesive matrix components, facilitating the partial detachment that is required for cell migration; (2) binding large amounts of water, leading to expansion of the tissue space that separates cellular or fibrous elements, thereby forming pathways for cell migration; and (3) interacting with HA-binding proteins such as RHAMM47 48 and CD 44.16 Not only is RHAMM expressed during SMC migration, but it also appears to be functionally required for migration of these cells, since antibodies to RHAMM block arterial SMC migration.49 Evidence also indicates that synthesis of HA is required for cell proliferation in vitro13 50 and is increased in proliferating cultured arterial SMCs.51

The opportunity to evaluate the temporal evolution of HA at predetermined times in an experimental model such as the balloon-injured rat carotid artery provides a perspective not available from analysis of human specimens at a single time. This is particularly true of "biopsies" obtained by directional atherectomy, since the intervention, in the case of restenosis, is limited to the point in each patient's history that presumably represents the zenith of the clinical symptoms and, by extrapolation, lesion redevelopment. It is likely that the HA deposits, like the PCNA evidence of cellular proliferation, represents the residual tail of activity responsible for the restenotic lesion. Indeed, if one had the opportunity to examine these lesions at predetermined earlier times, as in the rat carotid artery, the extent of HA and PCNA staining might indeed have been even more extensive.

It is possible that replacement of an HA-rich, gel-like ECM by a collagen-rich, fibrous ECM is associated with contraction of the lesion and secondarily of the whole arterial cross-sectional area. A precedent for this phenomenon is suggested by the late phases of dermal wound healing, characterized by a contraction of the collagen matrix due to increased collagen cross-linking.52 53 The consequent increase in tensile strength and stiffness also occurs in a variety of other fibrotic disorders.53

The water-binding capacity of HA-rich tissue not only explains the distinctive hue characteristic of FPT foci but also provides an intriguing basis for postangioplasty "geometric remodeling."54 This term has been used to describe chronic shrinkage in total cross-sectional arterial area after angioplasty, identified by intravascular ultrasound,55 and/or in necropsy studies involving animal models of restenosis.56 57 58 59

In summary, histological analyses of both rat and human lesions in the present study indicate that hyaluronan is a characteristic component of the distinctive extracellular matrix of fibroproliferative foci in human restenotic lesions. From a functional standpoint, hyaluronan may contribute to the pathogenesis of restenosis in at least two different ways. First, it may facilitate SMC migration and/or proliferation. Second, as a result of its ability to bind large amounts of water, accumulation of hyaluronan may contribute to volume expansion of intimal tissue and/or set the stage for "geometric remodeling" as the hyaluronan is replaced by a collagen ECM.


*    Selected Abbreviations and Acronyms
 
b-PG = biotinylated proteoglycan fragments
ECM = extracellular matrix
FPT = fibroproliferative tissue
HA = hyaluronic acid, hyaluronan
PCNA = proliferating cell nuclear antigen
RHAMM = receptor for HA-mediated motility


*    Acknowledgments
 
This work was supported in part by grant HL-40518 and an Academic Award in Vascular Medicine (HL-02824) from the NHLBI, NIH, Bethesda, Md. Dr Riessen was the recipient of a grant from the Deutsche Forschungsgemeinschaft, Bonn, Germany. We wish to thank Dr C. Underhill for providing the hyaluronan probe and Marianne Kearney and Eleanor Sullivan for expert technical assistance. Finally, we are indebted to Dr Barry L. Sharaf, Rhode Island Hospital, Providence, RI; Dr Christopher J. White, Ochsner Medical Institutions, New Orleans, La; Dr Gerald Zemel, Baptist Hospital, Miami, Fla; Dr Jacob Shani, Maimonides Medical Center, Brooklyn, NY; Dr Geoffrey O. Hartzler, St Luke's Hospital, Kansas City, Mo; Dr Michael Mooney, Minneapolis Heart Institute, Minn; Dr Ronald Masden, Jewish Hospital, Louisville, Ky; Dr Martin B. Leon, Washington (DC) Cardiology Center; and Dr Edward Kosinski, St Vincent's Medical Center, Bridgeport, Conn, for their cooperation in making available to us the coronary atherectomy specimens used in the present investigation.

Received July 24, 1995; revision received October 12, 1995; accepted October 20, 1995.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
up arrowDiscussion
*References
 

  1. Nobuyoshi M, Kimura T, Nosaka H. Restenosis after successful percutaneous transluminal coronary angioplasty: serial angiographic follow-up of 229 patients. J Am Coll Cardiol. 1988;12:616-623. [Abstract]
  2. Serruys PW, Luijten HE, Beat KJ, Geuskens R, De Feyter PJ, van den Brand M, Reiber JHC, ten Katen HJ, van Es GA, Hugenholtz PG. Incidence of restenosis after successful coronary angioplasty: a time-related phenomenon: a quantitative angiographic study in 342 consecutive patients at 1, 2, and 3 months. Circulation. 1988;77:361-372. [Abstract/Free Full Text]
  3. Nobuyoshi M, Kimura T, Ohishi H, Horiuchi H, Nosaka H, Hamasaki N, Yokoi H, Kim K. Restenosis after percutaneous transluminal coronary angioplasty: pathologic observations in 20 patients. J Am Coll Cardiol. 1990;17:433-439.
  4. Waller BF, Pinkerton CA, Orr CM, Slack JD, VanTassel JW, Peters T. Morphologic observations late (>30 days) after clinically successful coronary balloon angioplasty. Circulation. 1991;83(suppl I):I-28-I-41.
  5. Johnson DE, Hinohara T, Selmon MR, Braden W, Simpson JB. Primary peripheral arterial stenoses and restenoses excised by transluminal atherectomy: a histopathologic study. J Am Coll Cardiol. 1990;15:419-425. [Abstract]
  6. Garratt KN, Edwards WD, Kaufmann UP, Vlietstra RE, Holmes DR. Differential histopathology of primary atherosclerotic and restenotic lesions in coronary arteries and saphenous vein bypass grafts: analysis of tissue obtained from 73 patients by directional atherectomy. J Am Coll Cardiol. 1991;17:442-448. [Abstract]
  7. Miller MJ, Kuntz RE, Friedrich SP, Leidig GA, Fishman RF, Schnitt SJ, Baim DS, Safian RD. Frequency and consequences of intimal hyperplasia in specimens retrieved by directional atherectomy of native primary coronary artery stenoses and subsequent restenoses. Am J Cardiol. 1993;71:652-658. [Medline] [Order article via Infotrieve]
  8. Riessen R, Isner JM, Blessing E, Loushin C, Nikol S, Wight TN. Regional differences in the distribution of the proteoglycans biglycan and decorin in the extracellular matrix of atherosclerotic and restenotic human coronary arteries. Am J Pathol. 1994;144:962-974.[Abstract]
  9. Forrester JS, Fishbein M, Helfant R, Fagin J. A paradigm for restenosis based on cell biology: clues for the development of new preventive therapies. J Am Coll Cardiol. 1991;17:758-769. [Abstract]
  10. Schwartz RS, Holmes DR, Topol EJ. The restenosis paradigm revisited: an alternative proposal for cellular mechanisms. J Am Coll Cardiol. 1992;20:1284-1293. [Abstract]
  11. Hay ED. Cell Biology of Extracellular Matrix. New York, NY: Plenum Press; 1991.
  12. Toole BP. Proteoglycans and hyaluronan in morphogenesis and differentiation. In: Hay E, ed. Cell Biology of the Extracellular Matrix. New York, NY: Plenum Press; 1991:305-341.
  13. Laurent TC, Fraser TC. Hyaluronan. FASEB J. 1992;6:2397-2404. [Abstract]
  14. Rooney P, Kumar S. Inverse relationship between hyaluronan and collagens in development and angiogenesis. Differentiation. 1993;54:1-9. [Medline] [Order article via Infotrieve]
  15. Weigel PH, Fuller GM, LeBoeuf RD. A model for the role of hyaluronic acid and fibrin in the early events during the inflammatory response and wound healing. J Theor Biol. 1986;11:219-234.
  16. Sherman L, Sleeman J, Herrlich P, Ponta H. Hyaluronate receptors: key players in growth, differentiation, migration and tumor progression. Curr Opin Cell Biol. 1994;6:726-733. [Medline] [Order article via Infotrieve]
  17. Oksala O, Salo T, Tammi R, Häkkinen L, Jalkanen M, Inki P, Larjava H. Expression of proteoglycans and hyaluronan during wound healing. J Histochem Cytochem. 1995;43:125-135. [Abstract]
  18. Simpson JB, Selmon MR, Robertson GC, Cipriano PR, Hayden WG, Johnson DE, Fogarty TJ. Transluminal atherectomy for occlusive peripheral vascular disease. Am J Cardiol. 1988;61:96G-101G. [Medline] [Order article via Infotrieve]
  19. Safian RD, Gelbfish JS, Erny RE, Schmitt SJ, Schmidt DA, Baim DS. Coronary atherectomy: clinical, angiographic, and histological findings and observations regarding potential mechanisms. Circulation. 1990;82:69-79. [Abstract/Free Full Text]
  20. Clowes AW, Reidy MA, Clowes MM. Kinetics of cellular proliferation after arterial injury, I: smooth muscle cell growth in the absence of endothelium. Lab Invest. 1983;49:327-333. [Medline] [Order article via Infotrieve]
  21. Ripellino JA, Klinger MM, Margolis RU, Margolis RK. The hyaluronic acid binding region as a specific probe for the localization of hyaluronic acid in tissue sections. J Histochem Cytochem. 1985;33:1060-1066. [Abstract]
  22. Waldenström A, Martinussen HJ, Gerdin B, Hällgren R. Accumulation of hyaluronan and tissue edema in experimental myocardial infarction. J Clin Invest. 1991;88:1622-1628.
  23. Green SJ, Tarone G, Underhill CB. Distribution of hyaluronate and hyaluronate receptors in the adult lung. J Cell Sci. 1988;89:145-156.
  24. Shekonin BV, Domogatsky SP, Muzykantov VR, Idelson GL, Rukosuev VS. Distribution of type I, III, IV and V collagen in normal and atherosclerotic human arterial wall: immunomorphological characteristics. Collagen Rel Res. 1985;5:355-368.
  25. Godfrey M, Keene DR, Blank E, Hori H, Sakai LY, Sherwin LA, Hollister DW. Type II achondrogenesis-hypochondrogenesis: morphologic and immunohistopathologic studies. Am J Hum Genet. 1988;43:895-903.
  26. Tsukada T, Tippens D, Gordon D, Ross R, Gown AM. HHF35, a muscle-actin-specific monoclonal antibody, I: immunocytochemical and biochemical characterization. Am J Pathol. 1987;126:51-60. [Abstract]
  27. Gown AM, Tsukada T, Ross R. Human atherosclerosis, II: immunocytochemical analysis of the cellular composition of human atherosclerotic lesions. Am J Pathol. 1986;125:191-207. [Abstract]
  28. Pickering JG, Weir L, Jekanowski J, Kearney MA, Isner JM. Proliferative activity in peripheral and coronary atherosclerotic plaque among patients undergoing percutaneous revascularization. J Clin Invest. 1993;91:1469-1480.
  29. Hall P, Devison D, Woods A, Yu C-W, Kellock D, Watkins J, Barnes D, Gillet R, Camplejohn R, Waseem N, Lane D. Proliferating cell nuclear antigen (PCNA) immunolocalization in paraffin sections: an index of cell proliferation with evidence of deregulated expression in some neoplasms. J Pathol. 1990;162:285-294. [Medline] [Order article via Infotrieve]
  30. Gelb AB, Kamel OW, LeBrun DP, Warnke RA. Estimation of tumor growth fractions in archival formalin-fixed, paraffin-embedded tissues using two anti-PCNA/cyclin monoclonal antibodies. Am J Pathol. 1992;141:1453-1458. [Abstract]
  31. Rekhter M, Nicholls S, Ferguson M, Gordon D. Cell proliferation in human arteriovenous fistulas used for hemodialysis. Arterioscler Thromb. 1993;13:609-617. [Abstract/Free Full Text]
  32. O'Brien ER, Alpers CE, Stewart DK, Ferguson M, Tran N, Gordon D, Benditt EP, Hinohara T, Simpson JB, Schwartz SM. Proliferation in primary and restenotic coronary atherectomy tissue: implications for antiproliferative therapy. Circ Res. 1993;73:223-231. [Abstract/Free Full Text]
  33. Casscells W. Migration of smooth muscle and endothelial cells: critical events in restenosis. Circulation. 1992;86:723-729. [Free Full Text]
  34. Clark RAF, Henson PM. The Molecular and Cellular Biology of Wound Repair. New York, NY: Plenum Press; 1988.
  35. Gailit J, Clark RAF. Wound repair in the context of extracellular matrix. Curr Opin Cell Biol. 1994;6:717-725. [Medline] [Order article via Infotrieve]
  36. Ylä-Herttuala S, Sumuvuori H, Karkola K, Mötönen M, Nikkari T. Glycosaminoglycans in normal and atherosclerotic human coronary arteries. Lab Invest. 1986;54:402-407. [Medline] [Order article via Infotrieve]
  37. Heickendorff L, Ledet T, Rasmussen LM. Glycosaminoglycans in the human aorta in diabetes mellitus: a study of tunica media from areas with and without atherosclerotic plaque. Diabetologia. 1994;37:286-292. [Medline] [Order article via Infotrieve]
  38. Mayne R. Collagenous proteins of blood vessels. Arteriosclerosis. 1986;6:585-593. [Medline] [Order article via Infotrieve]
  39. Levesque H, Girard N, Maingonnat C, Delpech A, Chauzy C, Tayot J, Courtois H, Delpech B. Localization and solubilization of hyaluronan and of the hyaluronan-binding protein hyaluronectin in human normal and arteriosclerotic arterial walls. Atherosclerosis. 1994;105:51-62. [Medline] [Order article via Infotrieve]
  40. Jackson CL, Raines EW, Ross R, Reidy MA. Role of endogenous platelet-derived growth factor in arterial smooth muscle cell migration after balloon catheter injury. Arterioscler Thromb. 1993;13:1218-1226. [Abstract/Free Full Text]
  41. Clowes AW, Reidy MA, Clowes MM. Mechanisms of stenosis after arterial injury. Lab Invest. 1983;49:208-215. [Medline] [Order article via Infotrieve]
  42. Helin P, Lorenzen I, Garbarsch C, Mattiessen ME. Repair in arterial tissue: morphological and biochemical changes in rabbit aorta after a single dilation injury. Circ Res. 1971;29:542-554. [Abstract/Free Full Text]
  43. Heldin P, Laurent TC, Heldin CH. Effects of growth factors on hyaluronan synthesis in cultured human fibroblasts. Biochem J. 1989;258:919-922. [Medline] [Order article via Infotrieve]
  44. Samuel SK, Hurta RAR, Spearman MA, Wright JA, Turley EA, Greenberg AH. TGF-ß1 stimulation of cell locomotion utilizes the hyaluronate receptor RHAMM and hyaluronan. J Cell Biol. 1993;123:749-758. [Abstract/Free Full Text]
  45. Casscells W. Smooth muscle cell growth factors. Prog Growth Factor Res. 1991;3:177-206. [Medline] [Order article via Infotrieve]
  46. Boudreau N, Turley E, Rabinovitch M. Fibronectin, hyaluronan, and a hyaluronan binding protein contribute to increased ductus arteriosus smooth muscle cell migration. Dev Biol. 1991;143:235-247. [Medline] [Order article via Infotrieve]
  47. Hardwick C, Hoare K, Owens R, Hohn HP, Hook M, Moore D, Cripps V, Austen L, Nance DM, Turley EA. Molecular cloning of a novel hyaluronan receptor that mediates tumor cell motility. J Cell Biol. 1992;117:1343-1350. [Abstract/Free Full Text]
  48. Yang B, Yang BL, Savani RC, Turley EA. Identification of a common hyaluronan binding motif in the hyaluronan binding proteins RHAMM, CD44 and link protein. EMBO J. 1994;13:286-296. [Medline] [Order article via Infotrieve]
  49. Savani RC, Wang C, Yang B, Zhang S, Kinsella MG, Wight TN, Stern R, Nance DM, Turley EA. Migration of bovine aortic smooth muscle cells after wounding injury: the role of hyaluronan and RHAMM. J Clin Invest. 1995;95:1158-1168.
  50. Brecht M, Mayer U, Schlosser E, Prehm P. Increased hyaluronate synthesis is required for fibroblasts detachment and mitosis. Biochem J. 1986;239:445-450. [Medline] [Order article via Infotrieve]
  51. Deudon E, Berrou E, Breton M, Picard J. Growth-related production of proteoglycans and hyaluronic acid in synchronous arterial smooth muscle cells. Int J Biochem. 1992;24:465-470. [Medline] [Order article via Infotrieve]
  52. Orgill D, Demling RH. Current concepts and approaches to wound healing. Crit Care Med. 1988;16:899-908. [Medline] [Order article via Infotrieve]
  53. Reiser KM, McCormick R, Rucker RB. Enzymatic and nonenzymatic cross-linking of collagen. FASEB J. 1992;6:2439-2449. [Abstract]
  54. Isner JM. Vascular remodeling. Circulation. 1994;89:2937-2941. [Free Full Text]
  55. Mintz GS, Kovach JA, Javier SP, Ditrano CJ, Leon MB. Geometric remodeling is the predominant mechanism of late lumen loss after coronary angioplasty. Circulation. 1993;88(suppl I):I-654. Abstract.
  56. Currier JW, Faxon DP. Restenosis after percutaneous transluminal coronary angioplasty: have we been aiming at the wrong target? J Am Coll Cardiol. 1995;25:516-520. [Abstract]
  57. Kakuta T, Currier JW, Haudenschild CC, Ryan TJ, Faxon DP. Differences in compensatory vessel enlargement, not intimal formation, account for restenosis after angioplasty in the hypercholesterolemic rabbit model. Circulation. 1994;89:2809-2815. [Abstract/Free Full Text]
  58. Post MJ, Borst C, Kuntz RE. The relative importance of arterial remodeling compared with intimal hyperplasia in lumen renarrowing after balloon angioplasty: a study in the normal rabbit and the hypercholesterolemic Yucatan micropig. Circulation. 1994;89:2816-2821. [Abstract/Free Full Text]
  59. Lafont A, Guzman LA, Whitlow PL, Goormastic M, Cornhill JF, Chisolm GM. Restenosis after experimental angioplasty: intimal, medial, and adventitial changes associated with constrictive remodeling. Circ Res. 1995;76:996-1002.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
D. Vigetti, M. Viola, E. Karousou, M. Rizzi, P. Moretto, A. Genasetti, M. Clerici, V. C. Hascall, G. De Luca, and A. Passi
Hyaluronan-CD44-ERK1/2 Regulate Human Aortic Smooth Muscle Cell Motility during Aging
J. Biol. Chem., February 15, 2008; 283(7): 4448 - 4458.
[Abstract] [Full Text] [PDF]

Home page
 J. Histochem. Cytochem.Home page
T. O. McDonald, R. G. Gerrity, C. Jen, H.-J. Chen, K. Wark, T. N. Wight, A. Chait, and K. D. O'Brien
Diabetes and Arterial Extracellular Matrix Changes in a Porcine Model of Atherosclerosis
J. Histochem. Cytochem., November 1, 2007; 55(11): 1149 - 1157.
[Abstract] [Full Text] [PDF]

Home page
 Eur Heart JHome page
H. M.M. van Beusekom, F. Saia, J. D. Zindler, P. A. Lemos, S. L. S.-t. Hoor, M. A.H. van Leeuwen, P. J. de Feijter, P. W. Serruys, and W. J. van der Giessen
Drug-eluting stents show delayed healing: paclitaxel more pronounced than sirolimus
Eur. Heart J., April 12, 2007; (2007) ehm064v1.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
L. Zhao, J. A. Hall, N. Levenkova, E. Lee, M. K. Middleton, A. M. Zukas, D. J. Rader, J. J. Rux, and E. Pure
CD44 Regulates Vascular Gene Expression in a Proatherogenic Environment
Arterioscler. Thromb. Vasc. Biol., April 1, 2007; 27(4): 886 - 892.
[Abstract] [Full Text] [PDF]

Home page
 J. Exp. Med.Home page
D. Sedding, J.-M. Daniel, L. Muhl, K. Hersemeyer, H. Brunsch, B. Kemkes-Matthes, R. C. Braun-Dullaeus, H. Tillmanns, T. Weimer, K. T. Preissner, et al.
The G534E polymorphism of the gene encoding the factor VII-activating protease is associated with cardiovascular risk due to increased neointima formation
J. Exp. Med., December 4, 2006; (2006) jem.20052546.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
G. Otsuka, R. Agah, A. D. Frutkin, T. N. Wight, and D. A. Dichek
Transforming Growth Factor Beta 1 Induces Neointima Formation Through Plasminogen Activator Inhibitor-1-Dependent Pathways
Arterioscler. Thromb. Vasc. Biol., April 1, 2006; 26(4): 737 - 743.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
M. van den Boom, M. Sarbia, K. von Wnuck Lipinski, P. Mann, J. Meyer-Kirchrath, B.H. Rauch, K. Grabitz, B. Levkau, K. Schror, and J.W. Fischer
Differential Regulation of Hyaluronic Acid Synthase Isoforms in Human Saphenous Vein Smooth Muscle Cells: Possible Implications for Vein Graft Stenosis
Circ. Res., January 6, 2006; 98(1): 36 - 44.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
K. Hayashi, H. Banno, K. Kadomatsu, Y. Takei, K. Komori, and T. Muramatsu
Antisense oligodeoxyribonucleotide as to the growth factor midkine suppresses neointima formation induced by balloon injury
Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2203 - H2209.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
S. Chai, Q. Chai, C. C. Danielsen, P. Hjorth, J. R. Nyengaard, T. Ledet, Y. Yamaguchi, L. M. Rasmussen, and L. Wogensen
Overexpression of Hyaluronan in the Tunica Media Promotes the Development of Atherosclerosis
Circ. Res., March 18, 2005; 96(5): 583 - 591.
[Abstract] [Full Text] [PDF]

Home page
 J. Histochem. Cytochem.Home page
R. D. Kenagy, J. W. Fischer, S. Lara, J. D. Sandy, A. W. Clowes, and T. N. Wight
Accumulation and Loss of Extracellular Matrix During Shear Stress-mediated Intimal Growth and Regression in Baboon Vascular Grafts
J. Histochem. Cytochem., January 1, 2005; 53(1): 131 - 140.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
A. Farb, F. D. Kolodgie, J.-Y. Hwang, A. P. Burke, K. Tefera, D. K. Weber, T. N. Wight, and R. Virmani
Extracellular Matrix Changes in Stented Human Coronary Arteries
Circulation, August 24, 2004; 110(8): 940 - 947.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
T. N. Wight and M. J. Merrilees
Proteoglycans in Atherosclerosis and Restenosis: Key Roles for Versican
Circ. Res., May 14, 2004; 94(9): 1158 - 1167.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
M. Sussmann, M. Sarbia, J. Meyer-Kirchrath, R.M. Nusing, K. Schror, and J.W. Fischer
Induction of Hyaluronic Acid Synthase 2 (HAS2) in Human Vascular Smooth Muscle Cells by Vasodilatory Prostaglandins
Circ. Res., March 19, 2004; 94(5): 592 - 600.
[Abstract] [Full Text] [PDF]

Home page
 J. Thorac. Cardiovasc. Surg.Home page
C. Bizekis, G. Pintucci, C. C. Derivaux, F. Saponara, J.-H. Kim, K. M. Hyman, E. A. Grossi, F. G. Baumann, P. Mignatti, and A. C. Galloway
Activation of mitogen-activated protein kinases during preparation of vein grafts and modulation by a synthetic inhibitor
J. Thorac. Cardiovasc. Surg., September 1, 2003; 126(3): 659 - 665.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
I.-M. o Chung, H. K. Gold, S. M. Schwartz, Y. Ikari, M. A. Reidy, and T. N. Wight
Enhanced extracellular matrix accumulation in restenosis of coronary arteries after stent deployment
J. Am. Coll. Cardiol., December 18, 2002; 40(12): 2072 - 2081.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
B. Jian, J. Xu, J. Connolly, R. C. Savani, N. Narula, B. Liang, and R. J. Levy
Serotonin Mechanisms in Heart Valve Disease I: Serotonin-Induced Up-Regulation of Transforming Growth Factor-{beta}1 via G-Protein Signal Transduction in Aortic Valve Interstitial Cells
Am. J. Pathol., December 1, 2002; 161(6): 2111 - 2121.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
B. P. Toole, T. N. Wight, and M. I. Tammi
Hyaluronan-Cell Interactions in Cancer and Vascular Disease
J. Biol. Chem., February 8, 2002; 277(7): 4593 - 4596.
[Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
J. T. N. Tai, E. E. Brooks, S. Liang, R. Somogyi, J. D. Rosete, R. M. Lawn, and D. Shiffman
Determination of Temporal Expression Patterns for Multiple Genes in the Rat Carotid Artery Injury Model
Arterioscler. Thromb. Vasc. Biol., October 1, 2000; 20(10): 2184 - 2191.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
A. Chajara, M. Raoudi, B. Delpech, M. Leroy, J. P. Basuyau, and H. Levesque
Increased Hyaluronan and Hyaluronidase Production and Hyaluronan Degradation in Injured Aorta of Insulin-Resistant Rats
Arterioscler. Thromb. Vasc. Biol., June 1, 2000; 20(6): 1480 - 1487.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
L. C. FOSTER, P. WIESEL, G. S. HUGGINS, R. PAÑARES, M. T. CHIN, A. PELLACANI, and M. A. PERRELLA
Role of activating protein-1 and high mobility group-I(Y) protein in the induction of CD44 gene expression by interleukin-1{beta} in vascular smooth muscle cells
FASEB J, February 1, 2000; 14(2): 368 - 378.
[Abstract]