The restenosis paradigm revisited: an alternative proposal for cellular mechanisms
RS Schwartz,
DR Holmes Jr,
and
EJ Topol
Coronary restenosis is a reparative response to arterial injury during angioplasty, and remains a major clinical problem. The reasons for treatment failures likely stem from our incomplete understanding of the cellular mechanisms in restenotic neointimal formation. Restenosis is thought to result from migration and replication of medial smooth muscle cells to form an obstructive neointima, a concept neither observed nor demonstrated in humans. An alternative hypothesis for restenosis is based on observations in the porcine coronary injury model. In this model, there are three cellular stages in neointimal formation: thrombotic (stage I), cellular recruitment (stage II) and proliferative (stage III). The thrombotic stage occurs early and consists of platelets, fibrin and red blood cells accumulating at the vessel injury site. In the recruitment stage, the mural thrombus itself develops an endothelium, followed by a mononuclear leukocytic infiltrate beginning on the lumen side of the vessel. In the proliferative stage, a "cap" of actin-positive cells forms on the lumen surface and progressively thickens. These cells do not arise from media at the injury site. Extracellular matrix secretion and additional recruitment likely add to neointimal volume during this phase. Thrombus assumes a major role in restonosis by providing an absorbable matrix into which smooth muscle cells proliferate. Further studies are needed to validate or modify this hypothesis.
This article has been cited by other articles:

|
 |

|
 |
 
J. M. Wilson and J. T. Willerson
Myocardial Revascularization with Percutaneous Devices
Card. Surg. Adult,
January 1, 2008;
3(2008):
573 - 598.
[Full Text]
|
 |
|

|
 |

|
 |
 
S W Park, S H Lee, C H Kim, G S Jeon, S J Hong, J G Yi, and H J Jeon
Inhibition of pseudointimal hyperplasia in swine TIPS models: the efficacy of local delivery of paclitaxel using a perforated balloon catheter
Br. J. Radiol.,
September 1, 2007;
80(957):
702 - 707.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
K. Kusaba, H. Kai, M. Koga, N. Takayama, A. Ikeda, H. Yasukawa, Y. Seki, K. Egashira, and T. Imaizumi
Inhibition of Intrinsic Interferon-{gamma} Function Prevents Neointima Formation After Balloon Injury
Hypertension,
April 1, 2007;
49(4):
909 - 915.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
W. Yang, J. Ge, H. Liu, K. Zhao, X. Liu, X. Qu, W. Li, Y. Huang, A. Sun, and Y. Zou
Arsenic trioxide eluting stent reduces neointima formation in a rabbit iliac artery injury model
Cardiovasc Res,
December 1, 2006;
72(3):
483 - 493.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
L. S. M. Boesten, A. S. M. Zadelaar, A. van Nieuwkoop, L. Hu, J. Jonkers, B. van de Water, M. J. J. Gijbels, I. van der Made, M. P. J. de Winther, L. M. Havekes, et al.
Macrophage retinoblastoma deficiency leads to enhanced atherosclerosis development in ApoE-deficient mice
FASEB J,
May 1, 2006;
20(7):
953 - 955.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
A. G. Touchard and R. S. Schwartz
Preclinical Restenosis Models: Challenges and Successes
Toxicol Pathol,
January 1, 2006;
34(1):
11 - 18.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
X. Yang, D. P. Thomas, X. Zhang, B. W. Culver, B. M. Alexander, W. J. Murdoch, M. N.A. Rao, D. A. Tulis, J. Ren, and N. Sreejayan
Curcumin Inhibits Platelet-Derived Growth Factor-Stimulated Vascular Smooth Muscle Cell Function and Injury-Induced Neointima Formation
Arterioscler. Thromb. Vasc. Biol.,
January 1, 2006;
26(1):
85 - 90.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. Rahmani, J. T. Read, J. M. Carthy, P. C. McDonald, B. W. Wong, M. Esfandiarei, X. Si, Z. Luo, H. Luo, P. S. Rennie, et al.
Regulation of the Versican Promoter by the {beta}-Catenin-T-cell Factor Complex in Vascular Smooth Muscle Cells
J. Biol. Chem.,
April 1, 2005;
280(13):
13019 - 13028.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
A. Chandiwal, V. Balasubramanian, Z. K. Baldwin, M. S. Conte, and L. B. Schwartz
Gene Therapy for the Extension of Vein Graft Patency: A Review
Vascular and Endovascular Surgery,
January 1, 2005;
39(1):
1 - 14.
[Abstract]
[PDF]
|
 |
|

|
 |

|
 |
 
K. Toutouzas, A. Colombo, and C. Stefanadis
Inflammation and restenosis after percutaneous coronary interventions
Eur. Heart J.,
October 1, 2004;
25(19):
1679 - 1687.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
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]
|
 |
|

|
 |

|
 |
 
P. A. Kingston, S. Sinha, C. E. Appleby, A. David, T. Verakis, M. G. Castro, P. R. Lowenstein, and A. M. Heagerty
Adenovirus-Mediated Gene Transfer of Transforming Growth Factor-{beta}3, but Not Transforming Growth Factor-{beta}1, Inhibits Constrictive Remodeling and Reduces Luminal Loss After Coronary Angioplasty
Circulation,
December 2, 2003;
108(22):
2819 - 2825.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
Y. Izumi, S. Kim, M. Yoshiyama, Y. Izumiya, K. Yoshida, A. Matsuzawa, H. Koyama, Y. Nishizawa, H. Ichijo, J. Yoshikawa, et al.
Activation of Apoptosis Signal-Regulating Kinase 1 in Injured Artery and Its Critical Role in Neointimal Hyperplasia
Circulation,
December 2, 2003;
108(22):
2812 - 2818.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
N. Nili, A. N. Cheema, F. J. Giordano, A. W. Barolet, S. Babaei, R. Hickey, M. R. Eskandarian, M. Smeets, J. Butany, G. Pasterkamp, et al.
Decorin Inhibition of PDGF-Stimulated Vascular Smooth Muscle Cell Function: Potential Mechanism for Inhibition of Intimal Hyperplasia after Balloon Angioplasty
Am. J. Pathol.,
September 1, 2003;
163(3):
869 - 878.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
H. Teshima, N. Hayashida, H. Yano, M. Nishimi, E. Tayama, S. Fukunaga, H. Akashi, T. Kawara, and S. Aoyagi
Obstruction of St Jude medical valves in the aortic position: histology and immunohistochemistry of pannus
J. Thorac. Cardiovasc. Surg.,
August 1, 2003;
126(2):
401 - 407.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
A. Yamashita, Y. Asada, H. Sugimura, H. Yamamoto, K. Marutsuka, K. Hatakeyama, S. Tamura, Y. Ikeda, and A. Sumiyoshi
Contribution of von Willebrand Factor to Thrombus Formation on Neointima of Rabbit Stenotic Iliac Artery Under High Blood-Flow Velocity
Arterioscler. Thromb. Vasc. Biol.,
June 1, 2003;
23(6):
1105 - 1110.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
L. Mandinov, A. Mandinova, S. Kyurkchiev, D. Kyurkchiev, I. Kehayov, V. Kolev, R. Soldi, C. Bagala, E. D. de Muinck, V. Lindner, et al.
Copper chelation represses the vascular response to injury
PNAS,
May 27, 2003;
100(11):
6700 - 6705.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. R Bennett
IN-STENT STENOSIS: PATHOLOGY AND IMPLICATIONS FOR THE DEVELOPMENT OF DRUG ELUTING STENTS
Heart,
February 1, 2003;
89(2):
218 - 224.
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
A.H. Gomma, M.A. Elrayess, C.J. Knight, E. Hawe, K.M. Fox, and S.E. Humphries
The endothelial nitric oxide synthase (Glu298Asp and -786T>C) gene polymorphisms are associated with coronary in-stent restenosis
Eur. Heart J.,
December 2, 2002;
23(24):
1955 - 1962.
[Abstract]
[PDF]
|
 |
|

|
 |

|
 |
 
B. Liu, M. Fisher, and P. Groves
Down-regulation of the ERK1 and ERK2 mitogen-activated protein kinases using antisense oligonucleotides inhibits intimal hyperplasia in a porcine model of coronary balloon angioplasty
Cardiovasc Res,
June 1, 2002;
54(3):
640 - 648.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
J. Raymond, E. Sauvageau, I. Salazkin, E. Ribourtout, G. Gevry, and A.-C. Desfaits
Role of the Endothelial Lining in Persistence of Residual Lesions and Growth of Recurrences After Endovascular Treatment of Experimental Aneurysms
Stroke,
March 1, 2002;
33(3):
850 - 855.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
J. Raymond, P. Leblanc, A.-C. Desfaits, I. Salazkin, F. Morel, C. Janicki, and S. Roorda
In Situ Beta Radiation to Prevent Recanalization After Coil Embolization of Cerebral Aneurysms
Stroke,
February 1, 2002;
33(2):
421 - 427.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
J. Raymond, F. Berthelet, A.-C. Desfaits, I. Salazkin, and D. Roy
Cyanoacrylate Embolization of Experimental Aneurysms
AJNR Am. J. Neuroradiol.,
January 1, 2002;
23(1):
129 - 138.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
K. Kanamasa, Y. Inoue, N. Otani, N. Naito, H. Morii, A. Ikeda, M. Taniguchi, N. Ishida, T. Hayashi, and K. Ishikawa
tPA via Infusion Catheters Followed by Continuous IV Infusion for 3 Days Prevents Intimal Hyperplasia After Balloon Injury
Angiology,
December 1, 2001;
52(12):
819 - 825.
[Abstract]
[PDF]
|
 |
|

|
 |

|
 |
 
P. A. Kingston, S. Sinha, A. David, M. G. Castro, P. R. Lowenstein, and A. M. Heagerty
Adenovirus-Mediated Gene Transfer of a Secreted Transforming Growth Factor-{beta} Type II Receptor Inhibits Luminal Loss and Constrictive Remodeling After Coronary Angioplasty and Enhances Adventitial Collagen Deposition
Circulation,
November 20, 2001;
104(21):
2595 - 2601.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
R. S. Kellar, L. K. Landeen, B. R. Shepherd, G. K. Naughton, A. Ratcliffe, and S. K. Williams
Scaffold-Based Three-Dimensional Human Fibroblast Culture Provides a Structural Matrix That Supports Angiogenesis in Infarcted Heart Tissue
Circulation,
October 23, 2001;
104(17):
2063 - 2068.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
E.G. Zouridakis, R. Schwartzman, X. Garcia-Moll, I.D. Cox, S. Fredericks, D.W. Holt, and J.C. Kaski
Increased plasma endothelin levels in angina patients with rapid coronary artery disease progression
Eur. Heart J.,
September 1, 2001;
22(17):
1578 - 1584.
[Abstract]
[PDF]
|
 |
|

|
 |

|
 |
 
J. M. t. Berg, B. A. Hutten, J. C. Kelder, F. W. A. Verheugt, and H. W. T. Plokker
Oral Anticoagulant Therapy During and After Coronary Angioplasty : The Intensity and Duration of Anticoagulation Are Essential to Reduce Thrombotic Complications
Circulation,
April 24, 2001;
103(16):
2042 - 2047.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
A. Bayes-Genis, R. S. Schwartz, D. A. Lewis, M. T. Overgaard, M. Christiansen, C. Oxvig, K. Ashai, D. R. Holmes Jr, and C. A. Conover
Insulin-Like Growth Factor Binding Protein-4 Protease Produced by Smooth Muscle Cells Increases in the Coronary Artery After Angioplasty
Arterioscler. Thromb. Vasc. Biol.,
March 1, 2001;
21(3):
335 - 341.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
C. Napoli, G. Cirino, P. Del Soldato, R. Sorrentino, V. Sica, M. Condorelli, A. Pinto, and L. J. Ignarro
Effects of nitric oxide-releasing aspirin versus aspirin on restenosis in hypercholesterolemic mice
PNAS,
February 27, 2001;
98(5):
2860 - 2864.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
J. J. Popma, E. M. Ohman, J. Weitz, A. M. Lincoff, R. A. Harrington, and P. Berger
Antithrombotic Therapy in Patients Undergoing Percutaneous Coronary Intervention
Chest,
January 1, 2001;
119(1_suppl):
321S - 336S.
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
E. Sasaki, Y. Tanahashi, Y. Yamasaki, N. Oda, Y. Nozawa, H. Terakawa, K. Miyoshi, Y. Muranaka, H. Miyake, and N. Matsuura
Inhibitory Effect of TAS-301, a New Synthesized Constrictive Remodeling Regulator, on Renarrowing after Balloon Overstretch Injury of Porcine Coronary Artery
J. Pharmacol. Exp. Ther.,
December 1, 2000;
295(3):
1043 - 1050.
[Abstract]
[Full Text]
|
 |
|

|
 |

|
 |
 
S. L. Meyerson, C. L. Skelly, M. A. Curi, and L. B. Schwartz
Gene Therapy for Cardiovascular Disease
Seminars in Cardiothoracic and Vascular Anesthesia,
November 1, 2000;
4(4):
289 - 300.
[Abstract]
[PDF]
|
 |
|

|
 |

|
 |
 
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]
|
 |
|

|
 |

|
 |
 
N. Noiseux, C. H. Boucher, R. Cartier, and M. G. Sirois
Bolus Endovascular PDGFR-{beta} Antisense Treatment Suppressed Intimal Hyperplasia in a Rat Carotid Injury Model
Circulation,
September 12, 2000;
102(11):
1330 - 1336.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
Jianhua Zhu and Danchen Gao
Losartan reduces collagen content and intimal thickening of iliac arteries after balloon injury in rabbits
Journal of Renin-Angiotensin-Aldosterone System,
September 1, 2000;
1(3):
278 - 282.
[Abstract]
[PDF]
|
 |
|

|
 |

|
 |
 
J. M. t. Berg, J. C. Kelder, M. J. Suttorp, E. G. Mast, E. Bal, S. M. P. G. Ernst, F. W. A. Verheugt, and H. W. T. Plokker
Effect of Coumarins Started Before Coronary Angioplasty on Acute Complications and Long-Term Follow-Up : A Randomized Trial
Circulation,
July 25, 2000;
102(4):
386 - 391.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. V. Autieri, C. Carbone, and A. Mu
Expression of Allograft Inflammatory Factor-1 Is a Marker of Activated Human Vascular Smooth Muscle Cells and Arterial Injury
Arterioscler. Thromb. Vasc. Biol.,
July 1, 2000;
20(7):
1737 - 1744.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
A. Ehsan and M. J Mann
Antisense and gene therapy to prevent restenosis
Vascular Medicine,
May 1, 2000;
5(2):
103 - 114.
[Abstract]
[PDF]
|
 |
|

|
 |

|
 |
 
I. Ogawa, T. Hayashi, T. Nakabayashi, N. Otani, K. Ishikawa, and K. Kanamasa
Prevention of Coronary Arterial Renarrowing by Continuous 3-Day Infusion of Tissue Plasminogen Activator After Successful Percutaneous Transluminal Coronary Angioplasty: A Randomized, Double-Blind, Placebo-Controlled Study
Angiology,
May 1, 2000;
51(5):
367 - 375.
[Abstract]
[PDF]
|
 |
|

|
 |

|
 |
 
F.-J. Neumann, A. Kastrati, C. Schmitt, R. Blasini, M. Hadamitzky, J. Mehilli, M. Gawaz, M. Schleef, M. Seyfarth, J. Dirschinger, et al.
Effect of glycoprotein IIb/IIIa receptor blockade with abciximab on clinical and angiographic restenosis rate after the placement of coronary stents following acute myocardial infarction
J. Am. Coll. Cardiol.,
March 15, 2000;
35(4):
915 - 921.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
L. J. Feldman, L. Aguirre, M. Ziol, J.-P. Bridou, N. Nevo, J.-B. Michel, and P. G. Steg
Interleukin-10 Inhibits Intimal Hyperplasia After Angioplasty or Stent Implantation in Hypercholesterolemic Rabbits
Circulation,
February 29, 2000;
101(8):
908 - 916.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
J. M. Garasic, E. R. Edelman, J. C. Squire, P. Seifert, M. S. Williams, and C. Rogers
Stent and Artery Geometry Determine Intimal Thickening Independent of Arterial Injury
Circulation,
February 22, 2000;
101(7):
812 - 818.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
A.-C. Desfaits, J. Raymond, and J. P. Muizelaar
Growth Factors Stimulate Neointimal Cells In Vitro and Increase the Thickness of the Neointima Formed at the Neck of Porcine Aneurysms Treated by Embolization • Editorial Comment
Stroke,
February 1, 2000;
31(2):
498 - 507.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
C. Hehrlein, S. Kaiser, R. Riessen, J.u. Metz, P. Fritz, and W. Kubler
External beam radiation after stent implantation increases neointimal hyperplasia by augmenting smooth muscle cell proliferation and extracellular matrix accumulation
J. Am. Coll. Cardiol.,
August 1, 1999;
34(2):
561 - 566.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
P. Cirillo, P. Golino, M. Ragni, C. Battaglia, F. Pacifico, S. Formisano, C. Buono, M. Condorelli, and M. Chiariello
Activated platelets and leucocytes cooperatively stimulate smooth muscle cell proliferation and proto-oncogene expression via release of soluble growth factors
Cardiovasc Res,
July 1, 1999;
43(1):
210 - 218.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
C. Rogers, D. Y. Tseng, J. C. Squire, and E. R. Edelman
Balloon-Artery Interactions During Stent Placement : A Finite Element Analysis Approach to Pressure, Compliance, and Stent Design as Contributors to Vascular Injury
Circ. Res.,
March 5, 1999;
84(4):
378 - 383.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
I. J. Kullo, R. D. Simari, and R. S. Schwartz
Vascular Gene Transfer : From Bench to Bedside
Arterioscler. Thromb. Vasc. Biol.,
February 1, 1999;
19(2):
196 - 207.
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
T. Todaka, C. Yokoyama, H. Yanamoto, N. Hashimoto, I. Nagata, T. Tsukahara, S. Hara, T. Hatae, R. Morishita, M. Aoki, et al.
Gene Transfer of Human Prostacyclin Synthase Prevents Neointimal Formation After Carotid Balloon Injury in Rats • Editorial Comment
Stroke,
February 1, 1999;
30(2):
419 - 426.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. Labinaz, K. Pels, C. Hoffert, S. Aggarwal, and E. R O'Brien
Time course and importance of neoadventitial formation in arterial remodeling following balloon angioplasty of porcine coronary arteries
Cardiovasc Res,
January 1, 1999;
41(1):
255 - 266.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
R. Erbel, M. Haude, H. W. Hopp, D. Franzen, H. J. Rupprecht, B. Heublein, K. Fischer, P. de Jaegere, P. Serruys, W. Rutsch, et al.
Coronary-Artery Stenting Compared with Balloon Angioplasty for Restenosis after Initial Balloon Angioplasty
N. Engl. J. Med.,
December 3, 1998;
339(23):
1672 - 1678.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
H. M. Kwon, G. Sangiorgi, E. L. Ritman, A. Lerman, C. McKenna, R. Virmani, W. D. Edwards, D. R. Holmes, and R. S. Schwartz
Adventitial vasa vasorum in balloon-injured coronary arteries: Visualization and quantitation by a microscopic three-dimensional computed tomography technique
J. Am. Coll. Cardiol.,
December 1, 1998;
32(7):
2072 - 2079.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
K. E. Watson, F. Parhami, V. Shin, and L. L. Demer
Fibronectin and Collagen I Matrixes Promote Calcification of Vascular Cells in Vitro, Whereas Collagen IV Matrix Is Inhibitory
Arterioscler. Thromb. Vasc. Biol.,
December 1, 1998;
18(12):
1964 - 1971.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
Y. Nishimoto, Y. Miyazaki, Y. Toki, R. Murakami, M. Shinoda, A. Fukushima, and H. Kanayama
Enhanced secretion of insulin plays a role in the development of atherosclerosis and restenosis of coronary arteries: elective percutaneous transluminal coronary angioplasty in patients with effort angina
J. Am. Coll. Cardiol.,
November 15, 1998;
32(6):
1624 - 1629.
[Abstract]
[Full Text]
| |