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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:417-422.)
© 1997 American Heart Association, Inc.

Articles

Vascular Myofibroblasts

Lessons From Coronary Repair and Remodeling

Andrew Zalewski; ; Yi Shi

From the Department of Medicine (Cardiology), Thomas Jefferson University, Philadelphia, Pa.

Correspondence to Andrew Zalewski, MD, Cardiovascular Research Center, Division of Cardiology, Thomas Jefferson University, 1025 Walnut St, Suite 410N, Philadelphia, PA 19107.

Key Words: coronary artery • myofibroblast • smooth muscle • adventitia

	Introduction

Top Introduction Fibroblasts, Myofibroblasts, and... Are Myofibroblasts a... Myofibroblasts in Other... Future Directions Summary References

 
Vascular repair and remodeling represents a common theme of many cardiovascular abnormalities. This is not surprising, since frequent exposure of blood vessels to excessive hemodynamic stress (eg, hypertension), the noxious effects of blood contents (eg, atherogenic lipids), and locally released cytokines (eg, postangioplasty) require readily available mechanism(s) to counteract their adverse effects and to preserve the intactness of the vessel wall. These responses, which were evolutionarily developed to repair an injured tissue, often escape self-limiting control and result in lumen narrowing. Various vascular lesions contain mesenchymal cells, different from normal medial cells, which has been viewed as evidence that smooth muscle (SM) cells modulate their phenotype in response to changes in the environment in situ.^{1 2 3} This concept has been further reinforced by the dedifferentiation of SM cells to a "synthetic" phenotype in culture.⁴ The presence of "nonmuscle" cells in the normal vessel wall, however, raises an intriguing question regarding whether they contribute to vascular repair while acquiring markers of muscle differentiation. This review will examine the potential role of these cells in coronary repair and remodeling.

Seminal studies by Gabbiani and coworkers^{5 6} have established that wound healing is associated with rapid activation of fibroblasts, which proliferate, migrate, and undergo differentiation to myofibroblasts. These cells acquire bundles of microfilaments (stress fibers) and develop extensive connections with the surrounding extracellular matrix, a change which is consistent with the primary role of newly formed myofibroblasts to close an open wound by means of extracellular matrix protein synthesis and contraction.⁷ Subsequent studies have confirmed the pivotal role of myofibroblasts in a wide range of other pathological conditions associated with fibrogenesis and organ remodeling.^{8 9 10 11} Although myofibroblasts from such diverse sources are heterogeneous, their common feature is the expression of -SM actin.¹² When wound healing is completed, myofibroblasts are usually eliminated by apoptosis,⁶ except in cases of so-called fibrocontractive disorders, in which their presence is sustained, leading to organ fibrosis and/or constrictive remodeling.^{8 13} The ubiquitous formation of myofibroblasts reflects a common mechanism of tissue repair, which raises the fundamental question of whether a similar phenomenon occurs in the vessel wall in response to injury. In the normal artery, nonmuscle cells are primarily found in the adventitia, which also contains vasa vasorum and rich sympathetic innervation. Since activated fibroblasts are notorious for their ability to acquire not only -SM actin but also several other markers of muscle differentiation,¹² the presence of myofibroblasts in the vessel wall can be easily overlooked and their impact on vascular repair attributed to abundant SM cells.

	Fibroblasts, Myofibroblasts, and Coronary Restenosis

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Adventitial Response to Injury
In porcine coronary vasculature, balloon-induced injury often results in medial dissection and exposure of the adventitia to the lumen. This condition initiates a chain of events reminiscent of the wound-healing process. Cell proliferation is the early phenomenon, which involves the entire adventitia, with the majority of cells representing activated fibroblasts (see the Figure, A). This burst of proliferation is short-lived, lasting 1 week.¹⁴ Coronary media shows a significantly lower level of cell proliferation at any time point, consistent with a higher degree of differentiation of resident SM cells. The activation of fibroblasts is accompanied by their differentiation to myofibroblasts, with the appearance of -SM actin in the adventitia beginning at 3 days and reaching a maximum at 7 to 14 days (Figure, B).^{14 15} Thus, fibroblasts acquire some markers of muscle differentiation, whereas medial SM cells are known to exhibit a loss of -SM actin expression after arterial injury.^{1 16} Phenotypic changes affecting adventitial cells are accompanied by the induction of procollagen 1(I) mRNA and intracellular protein in fibroblasts and later in myofibroblasts (Figure, C). This is followed by the deposition of mature extracellular collagen, which is abundant in the adventitia at later times (1 month). The activation of adventitial fibroblasts results in focal enlargement of the adventitia, initially due to its hypercellularity and tissue edema, followed by the development of a collagen-rich scar.^{14 17} In contrast to these dynamic changes, the media exhibits much less pronounced alterations in collagen synthesis.¹⁷

View larger version (138K): [in this window] [in a new window]   Figure 1. Response of porcine coronary arteries to balloon-induced injury. A, Adventitial cell proliferation. BrdU-positive cells (dark nuclei) are abundant in the adventitia after its exposure to the lumen. Note relatively few labeled cells in the injured media (2 days after angioplasty). B, Myofibroblast formation. Activated adventitial fibroblasts acquire -SM actin (red stain) in the vicinity of arterial injury. Note the formation of the neointima, which fills the gap between the edges of the media (8 days after angioplasty). C, Synthetic phenotype. Activated adventitial fibroblasts exhibit markedly upregulated expression of procollagen 1(I) (brown stain). Note lower basal expression of procollagen 1(I) in the media (2 days after angioplasty). D, TGFß1 expression. Coronary injury induces intracellular TGFß1 in activated adventitial fibroblasts (2 days after angioplasty). E, Contribution of adventitial myofibroblasts to neointimal formation. Adventitial fibroblasts labeled with BrdU (see A) extend contiguously from the adventitia to neointima. Note that the adjacent media (arrows) continues to show fewer labeled cells (8 days after angioplasty). F, Constrictive remodeling. Severe luminal narrowing of injured coronary artery, with bright areas corresponding to mature extracellular collagen (polarizing light microscopy of Sirius red stain). Note a predominant collagen deposition in a large adventitia (12 months after angioplasty). a indicates adventitia; m, media; and n, neointima. Magnifications: A through D x120, F x17.

Remodeling of the adventitia raises questions as to the factors that initiate and then sustain this response. Several cytokines released from platelets or cell debris, and thrombin itself, which is deposited at the site of balloon injury, undoubtedly contribute to the initial wave of cell proliferation. Cell proliferation alone, however, cannot entirely explain adventitial changes after coronary injury. The expression of transforming growth factor (TGF) ß1, which is rapidly induced in injured coronary adventitia (Figure, D), may provide a differentiation signal for fibroblasts to acquire -SM actin,¹⁸ analogous to the induction of myodifferentiation in nonvascular tissues, or even in medial SM cells.^{19 20} In injured coronary arteries, the autocrine TGFß1 expression is highly localized to adventitial myofibroblasts, which reflects the ability of TGFß1 to exert profibrotic and remodeling effects mediated by myofibroblasts. The ultrastructural characteristics of these cells demonstrate the abundance of stress fibers and dilated rough endoplasmic reticulum, reminiscent of myofibroblasts originally described in wound healing.¹⁸

Neointima and Its Origin
The mere presence of -SM actin does not necessarily reflect the SM origin of neointimal cells, since markers of muscle differentiation (even desmin) can be acquired by the adjacent adventitial fibroblasts (Table).^{14 15} Furthermore, various perivascular manipulations have been reported to induce the neointima or conversely, adventitial applications of antiproliferative agents decreased tissue growth at the luminal surface in some animal models.^{21 22 23} These observations raise a provocative question regarding whether myofibroblasts derived from adventitial cells contribute to neointimal formation after severe medial injury, analogous to activated wound fibroblasts invading the site of tissue loss. Alternatively, the role of myofibroblasts could be limited to adventitial remodeling, and the neointima may be solely derived from the edges of disrupted media. The relationship between the adventitial exposure to the lumen and neointimal formation suggests the contribution of myofibroblasts to luminal repair.^{14 24 25} When activated adventitial fibroblasts are labeled with bromodeoxyuridine (BrdU), which exploits their early proliferation, labeled cells acquire -SM actin, traverse the external elastic lamina, and then appear in the neointima (Figure, E).^{15 25} Although the precise number of translocating adventitial cells and their ultimate fate are difficult to assess, it is striking that the portions of the intact media appear to serve as a barrier, preventing the activated cells from migrating.²⁵ Consistent with the above observations, when the coronary media and adventitia are separated and then examined in organ culture, the latter demonstrates preferential outward cell migration. This is paralleled by higher activity of matrix-degrading metalloproteinases released from the adventitia. Conversely, the media synthesizes more of the inhibitor of matrix metalloproteinases, which may contribute to less accentuated migration of medial SM cells (Y.S., unpublished data, 1997). It is important to underscore that the above observations do not preclude the participation of medial SM cells released from the protective sheath of basal membrane at the edges of disrupted media.

View this table: [in this window] [in a new window]   Table 1. Distribution of Cytoskeletal Protein Markers in Medial SM Cells and Myofibroblasts of Different Origin

Constrictive Remodeling
Recent experimental and clinical findings have challenged the previously accepted view that luminal narrowing (ie, restenosis) is solely due to the growth of neointima after transcatheter interventions.^{26 27} In fact, early formation of neointima is often associated with compensatory vessel enlargement followed by shrinkage of the arterial cross-sectional area. This observation raises the possibility that adventitial myofibroblasts contribute to this process, analogous to their nonvascular counterparts, which reduce dimensions of collagen gels ex vivo and produce wound contraction in vivo. The remodeling properties of myofibroblasts are related to the presence of -SM actin, inasmuch as its depolymerization abrogates this phenomenon in vitro.²⁸ In addition, the expression of integrins is likely involved, allowing for specific cell-matrix interactions. Although adventitial myofibroblasts are the major source of collagen and may initiate its reorganization after coronary injury, other factors should also be considered. In contrast to wound contraction, adventitial myofibroblasts are largely absent at the time of the most notable constrictive arterial remodeling (3 months) (Figure, F). This factor suggests that further realignment of collagenous scar and intermolecular cross-linking continue within the adventitia at the time of cellular quiescence.

	Are Myofibroblasts a Model-Dependent Phenomenon?

Top Introduction Fibroblasts, Myofibroblasts, and... Are Myofibroblasts a... Myofibroblasts in Other... Future Directions Summary References

 
The complexity of human vascular lesions opens to criticism the findings regarding any mechanisms of vascular repair derived from animal models. This skepticism is further amplified by the failure of presumed therapies, which are effective in small animals (eg, rat), to translate to a clinical benefit in the prevention of coronary restenosis in patients. Thus, it is important to critically consider whether vascular myofibroblasts represent a model-dependent phenomenon or whether the conditions for their presence actually exist in patients with cardiovascular disorders.

Species Differences
Invaluable lessons concerning vascular repair have been learned from many pioneering studies using small animal models (eg, rat, rabbit).^{16 29 30} Without denying their importance, however, the concern can be raised whether they are fully representative of coronary arterial repair. Different degrees of SM cell differentiation in lower species may explain higher proliferation rates of medial cells and the ensuing neointimal formation without adventitial exposure to the lumen. In larger animals (and presumably in humans), arterial injury devoid of medial dissection induces only a small neointima.²⁵ Its origin has been recently linked to cellular heterogeneity of the media, which appears to contain sparse nonmuscle cells.³¹ These cells are virtually identical to adventitial fibroblasts but differ from enzymatically isolated medial SM cells, which are less likely to proliferate or adhere. In addition to species-dependent considerations, well-recognized changes in the phenotype of cultured SM cells could be accentuated by their release from the stabilizing effects of the basal membrane in vitro or they may represent the selection of myofibroblasts that are more responsive to proliferative stimuli.³¹

Severity of Injury
The interruption of the media and the exposure of the adventitia to the lumen are important for the rapid induction of myofibroblast phenotype in balloon-injured porcine coronary arteries. Likewise, coronary angioplasty in patients appears to result in vascular injury extending to the adventitia, most often unrecognized angiographically.³ Furthermore, intracoronary stent deployment, which requires high pressure expansion, conceivably results in even more extensive exposure of the adventitia. Although stents reduce the rate of restenosis in patients owing to a larger acute gain and the elimination of constrictive remodeling, the permanent implantation of a foreign body increases the local thrombotic and inflammatory responses, which may augment myofibroblast migration.

Coronary Versus Noncoronary Vasculature
Since coronary restenosis remains the "Achilles' heel" of transcatheter coronary interventions, regional differences in response to vascular injury should also be taken into consideration. Coronary arteries differ from the aorta or peripheral arteries with regard to fetal development, postnatal histological architecture, and cytoskeletal characteristics of the resident cells.^{32 33} These factors suggest that the arterial "substrate" may influence the contribution of myofibroblasts in coronary arterial repair as well as provide the explanation for regional differences in the propensity to develop atherosclerotic lesions.

	Myofibroblasts in Other Cardiovascular Abnormalities

Top Introduction Fibroblasts, Myofibroblasts, and... Are Myofibroblasts a... Myofibroblasts in Other... Future Directions Summary References

 
Vein Graft Remodeling
Venous grafts undergo remodeling changes after their placement in the arterial system. In a porcine model of saphenous vein graft interposition in the carotid artery, the perigraft "wound" is transiently populated by myofibroblasts, which surround the vein and are subsequently replaced by the collagenous scar commonly encountered during reoperations.³⁴ These changes may contribute to the failure of aortocoronary saphenous vein grafts to undergo compensatory dilation when atherosclerotic lesions begin to compromise the lumen.³⁵ The activation of the perigraft fibroblasts brings to question the origin of the intima that almost invariably develops after these procedures. When perigraft fibroblasts are selectively labeled at the time of their proliferation, they appear to migrate through the media to the luminal surface, changing their phenotype to myofibroblasts. This process is facilitated by unavoidable medial injury induced by harvesting and the intraoperative storage of venous conduits as well as by a high number of reactive nonmuscle cells normally present in venous media (25%).³⁶

Atherosclerosis
The development of atherosclerosis is tightly linked to the existence of intima, which has provided the basis for its recent description as the "soil" for atherosclerosis.³⁷ If adventitial or medial fibroblasts can acquire several characteristics of synthetic SM-like cells, their subsequent migration and synthetic capabilities could favor lipid retention, leading to lesion development over the course of several decades. Interestingly, the application of the inflammatory cytokine interleukin-1ß to the adventitia induces coronary vasospasm and neointimal formation even without endoluminal manipulations in pigs.³⁸ These findings bear relevance to clinical settings, since the accumulation of mast cells and the inflammatory reaction in the adventitia are notable in patients with coronary vasospasm and fatal unstable coronary syndromes, respectively.^{39 40} Several adhesion molecules are highly expressed in intimal neovasculature and adventitial vasa vasorum of human coronary lesions, suggesting the presence of additional routes for inflammatory cell recruitment into developing atherosclerotic plaque.⁴¹ Although the exact cause of these changes remains to be determined, the adventitia may serve as a reservoir for several cytokines that may initiate the activation of the surrounding fibroblasts.

Myocardial Remodeling
Left ventricular remodeling is a common response to hypertension and myocardial infarction. The accompanying increase in collagen content contributes to abnormal left ventricular function. In experimental renovascular hypertension, progressive scarring of the adventitia of intramyocardial coronary arteries is associated with the outward extension of collagen deposition into the interstitial space.⁴² A different mechanism is involved after myocardial infarction in which interstitial myofibroblasts with abundant collagen expression appear to have a sustained presence.¹³

	Future Directions

Top Introduction Fibroblasts, Myofibroblasts, and... Are Myofibroblasts a... Myofibroblasts in Other... Future Directions Summary References

 
Myofibroblast Identification
Earlier studies have shown that -SM actin–expressing cells, derived from several nonvascular tissues, are of fibroblast origin and do not represent the admixture by SM cells or pericytes.⁴³ In the cardiovascular system, the identification of myofibroblasts has been even more challenging because of the abundance of medial SM cells. The recognition of myofibroblasts has been based on spatial (eg, adventitia) and temporal (eg, after arterial injury) changes in the expression of cytoskeletal markers (mainly -SM actin).^{14 15 25 31} In addition, ultrastructural characteristics and the synthesis of extracellular matrix proteins aid in the recognition of these cells.^{17 18} There is clearly the need for better cytoskeletal or molecular markers that can distinguish the spectrum of myofibroblast phenotypes from medial SM cells to discern their respective contributions in several cardiovascular abnormalities.

Therapeutic Implications
The activation of adventitial fibroblasts after experimental balloon-induced coronary injury raises the possibility of therapeutic targeting of this response for the prevention of coronary restenosis. Critical issues that need to be resolved include the selection of inhibitor(s) and the mode of delivery. Several synthetic DNA-based compounds ("antisense") directed against cell-cycle-regulating genes have been proposed to abolish a short-lived cell proliferation. These pleiotropic agents have also demonstrated growth factor–binding properties, which enhance their antiproliferative effects.⁴⁴ The alternative may involve the inhibition of TGFß1 and fibroblast differentiation, which has shown promising results in nonvascular applications.⁴⁵ The need for a single endoluminal delivery of therapeutic compounds into relatively inaccessible adventitia, however, remains the major challenge for these strategies. Intracoronary stenting may provide an advantage by allowing for more aggressive drug delivery without the risk of abrupt vessel closure. The future development of technologies for stent coating and the elution of desired agents promises to prolong the bioavailability of locally administered compounds. Some of the above difficulties can be alleviated by the application of a unique form of "local" therapy, ie, intracoronary radiation (brachytherapy). A recent report has suggested the attenuation of adventitial activation as a potential explanation for the encouraging preclinical effects of this approach postangioplasty.⁴⁶

Pharmacological targeting of activated fibroblasts during bypass surgery with saphenous vein grafts (ie, vein graft "engineering") may offer some advantages compared with the strategies directed toward the prevention of coronary restenosis. The delivery of inhibitor(s) is less problematic, since the harvested vein and the perigraft region are obviously more accessible to therapies during a surgical procedure. The fundamental issue whether a single application of a therapeutic agent is sufficient to control a chronic process will require careful studies.

	Summary

Top Introduction Fibroblasts, Myofibroblasts, and... Are Myofibroblasts a... Myofibroblasts in Other... Future Directions Summary References

 
Recent findings demonstrate that adventitial fibroblasts (ie, nonmuscle cells) are endowed with several characteristics previously attributed to medial SM cells. The response of the coronary artery to balloon angioplasty is associated with the activation of adventitial cells in a porcine model. They appear to be the most reactive in the arterial wall, as reflected by the extent of proliferation and the synthesis of collagen. Differentiation of adventitial cells, which acquire -SM actin, illustrates the formation of vascular myofibroblasts, a ubiquitous cellular mechanism of tissue repair. Myofibroblasts are involved in remodeling of the adventitia and may contribute to the formation of the neointima after balloon-induced coronary injury. These findings suggest that at least some synthetic SM-like cells present in intimal lesions may originate from medial or adventitial nonmuscle cells. Myofibroblasts also appear to play a role in other cardiovascular abnormalities (eg, vein graft remodeling), which raises the possibility of targeted therapies.

	Acknowledgments

 
This study was supported in part by grants from the National Institutes of Health (HL-44150) and the American Heart Association, Delaware and Florida Affiliates, Inc. The authors acknowledge the contributions of John D. Mannion, MD; James E. O'Brien, Jr, MD; and Wooksung Chung, MD, in the studies regarding vein graft remodeling.

Received December 13, 1996; accepted January 13, 1997.

	References

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				M. Puato, C. Piergentili, M. Zanardo, R. Rocchi, M. Giordan, P. Cardaioli, and P. Pauletto Vascular Remodeling After Carotid Artery Stenting Angiology, November 1, 2007; 58(5): 565 - 571. [Abstract] [PDF]

				L. Li, C. M. Terry, D. K. Blumenthal, T. Kuji, T. Masaki, B. C. H. Kwan, I. Zhuplatov, J. K. Leypoldt, and A. K. Cheung Cellular and morphological changes during neointimal hyperplasia development in a porcine arteriovenous graft model Nephrol. Dial. Transplant., November 1, 2007; 22(11): 3139 - 3146. [Abstract] [Full Text] [PDF]

				Q. Gan, T. Yoshida, J. Li, and G. K. Owens Smooth Muscle Cells and Myofibroblasts Use Distinct Transcriptional Mechanisms for Smooth Muscle {alpha}-Actin Expression Circ. Res., October 26, 2007; 101(9): 883 - 892. [Abstract] [Full Text] [PDF]

				K. Maiellaro and W. R. Taylor The role of the adventitia in vascular inflammation Cardiovasc Res, September 1, 2007; 75(4): 640 - 648. [Abstract] [Full Text] [PDF]

				R. C.M. Siow and A. T. Churchman Adventitial growth factor signalling and vascular remodelling: Potential of perivascular gene transfer from the outside-in Cardiovasc Res, September 1, 2007; 75(4): 659 - 668. [Abstract] [Full Text] [PDF]

				S. J. An, R. Boyd, M. Zhu, A. Chapman, D. R. Pimentel, and H. D. Wang NADPH oxidase mediates angiotensin II-induced endothelin-1 expression in vascular adventitial fibroblasts Cardiovasc Res, September 1, 2007; 75(4): 702 - 709. [Abstract] [Full Text] [PDF]

				J. S. Garanich, R. A. Mathura, Z.-D. Shi, and J. M. Tarbell Effects of fluid shear stress on adventitial fibroblast migration: implications for flow-mediated mechanisms of arterialization and intimal hyperplasia Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H3128 - H3135. [Abstract] [Full Text] [PDF]

				M. Weaver, J. Liu, D. Pimentel, D. J. Reddy, P. Harding, E. L. Peterson, and P. J. Pagano Adventitial delivery of dominant-negative p67phox attenuates neointimal hyperplasia of the rat carotid artery Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1933 - H1941. [Abstract] [Full Text] [PDF]

				A K Mitra and D K Agrawal In stent restenosis: bane of the stent era. J. Clin. Pathol., March 1, 2006; 59(3): 232 - 239. [Abstract] [Full Text] [PDF]

				A. S. Blom, R. Mukherjee, J. J. Pilla, A. S. Lowry, W. M. Yarbrough, J. T. Mingoia, J. W. Hendrick, R. E. Stroud, J. E. McLean, J. Affuso, et al. Cardiac Support Device Modifies Left Ventricular Geometry and Myocardial Structure After Myocardial Infarction Circulation, August 30, 2005; 112(9): 1274 - 1283. [Abstract] [Full Text] [PDF]

				T. Schachner, A. Oberhuber, Y. Zou, A. Tzankov, H. Ott, G. Laufer, and J. Bonatti Rapamycin treatment is associated with an increased apoptosis rate in experimental vein grafts Eur. J. Cardiothorac. Surg., February 1, 2005; 27(2): 302 - 306. [Abstract] [Full Text] [PDF]

				J. Herrmann, S. Samee, A. Chade, M. R. Porcel, L. O. Lerman, and A. Lerman Differential Effect of Experimental Hypertension and Hypercholesterolemia on Adventitial Remodeling Arterioscler. Thromb. Vasc. Biol., February 1, 2005; 25(2): 447 - 453. [Abstract] [Full Text] [PDF]

				B. Somoza, M. C. Gonzalez, J. M. Gonzalez, F. Abderrahim, S. M. Arribas, and M. S. Fernandez-Alfonso Modulatory role of the adventitia on noradrenaline and angiotensin II responses: Role of endothelium and AT2 receptors Cardiovasc Res, February 1, 2005; 65(2): 478 - 486. [Abstract] [Full Text] [PDF]

				H. M. Dourron, G. M. Jacobson, J. L. Park, J. Liu, D. J. Reddy, M. L. Scheel, and P. J. Pagano Perivascular gene transfer of NADPH oxidase inhibitor suppresses angioplasty-induced neointimal proliferation of rat carotid artery Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H946 - H953. [Abstract] [Full Text] [PDF]

				S. V. Subramanian, J. A. Polikandriotis, R. J. Kelm Jr., J. J. David, C. G. Orosz, and A. R. Strauch Induction of Vascular Smooth Muscle {alpha}-Actin Gene Transcription in Transforming Growth Factor {beta}1-Activated Myofibroblasts Mediated by Dynamic Interplay between the Pur Repressor Proteins and Sp1/Smad Coactivators Mol. Biol. Cell, October 1, 2004; 15(10): 4532 - 4543. [Abstract] [Full Text] [PDF]

				Y. Xu, H. Arai, X. Zhuge, H. Sano, T. Murayama, M. Yoshimoto, T. Heike, T. Nakahata, S.-i. Nishikawa, T. Kita, et al. Role of Bone Marrow-Derived Progenitor Cells in Cuff-Induced Vascular Injury in Mice Arterioscler. Thromb. Vasc. Biol., March 1, 2004; 24(3): 477 - 482. [Abstract] [Full Text]

				R. C.M Siow, C. M Mallawaarachchi, and P. L Weissberg Migration of adventitial myofibroblasts following vascular balloon injury: insights from in vivo gene transfer to rat carotid arteries Cardiovasc Res, July 1, 2003; 59(1): 212 - 221. [Abstract] [Full Text] [PDF]

				F. E. Rey and P. J. Pagano The Reactive Adventitia: Fibroblast Oxidase in Vascular Function Arterioscler. Thromb. Vasc. Biol., December 1, 2002; 22(12): 1962 - 1971. [Abstract] [Full Text] [PDF]

				Y. Nakazato, Y. Yamaji, N. Oshima, M. Hayashi, and T. Saruta Calcification and osteopontin localization in the peritoneum of patients on long-term continuous ambulatory peritoneal dialysis therapy Nephrol. Dial. Transplant., July 1, 2002; 17(7): 1293 - 1303. [Abstract] [Full Text] [PDF]

				E. Mori, K. Komori, T. Yamaoka, M. Tanii, C. Kataoka, A. Takeshita, M. Usui, K. Egashira, and K. Sugimachi Essential Role of Monocyte Chemoattractant Protein-1 in Development of Restenotic Changes (Neointimal Hyperplasia and Constrictive Remodeling) After Balloon Angioplasty in Hypercholesterolemic Rabbits Circulation, June 18, 2002; 105(24): 2905 - 2910. [Abstract] [Full Text] [PDF]

				S. V. Subramanian, R. J. Kelm Jr., J. A. Polikandriotis, C. G. Orosz, and A. R. Strauch Reprogramming of vascular smooth muscle {alpha}-actin gene expression as an early indicator of dysfunctional remodeling following heart transplant Cardiovasc Res, June 1, 2002; 54(3): 539 - 548. [Abstract] [Full Text] [PDF]

				S. Sartore, A. Chiavegato, E. Faggin, R. Franch, M. Puato, S. Ausoni, and P. Pauletto Contribution of Adventitial Fibroblasts to Neointima Formation and Vascular Remodeling: From Innocent Bystander to Active Participant Circ. Res., December 7, 2001; 89(12): 1111 - 1121. [Abstract] [Full Text] [PDF]

				F. J. Miller Jr Adventitial Fibroblasts : Backstage Journeymen Arterioscler. Thromb. Vasc. Biol., May 1, 2001; 21(5): 722 - 723. [Full Text] [PDF]

				M. A. Albassam, A. L. Metz, R. E. Potoczak, K. P. Gallagher, S. Haleen, H. Hallak, and E. J. Mcguire Studies on Coronary Arteriopathy in Dogs Following Administration of CI-1020, an Endothelin A Receptor Antagonist Toxicol Pathol, April 1, 2001; 29(3): 277 - 284. [Abstract] [PDF]