© 1999 American Heart Association, Inc.
Original Contribution |
Soluble Transforming Growth Factor-ß Type II Receptor Inhibits Negative Remodeling, Fibroblast Transdifferentiation, and Intimal Lesion Formation But Not Endothelial Growth
From the Center for Molecular Medicine (J.D.S., S.R.B., L.L.C., C.P.H.V., V.L.), Maine Medical Center Research Institute, South Portland, Me, and Biogen, Inc (P.J.G., V.E.K.), Cambridge, Mass.
Correspondence to Volkhard Lindner, Center for Molecular Medicine, Maine Medical Center Research Institute, 125 John Roberts Rd, Suite 12, South Portland, ME 04106. E-mail lindnv{at}poa.mmc.org
Abstract—Using the rat balloon
catheter denudation model, we examined the role of transforming growth
factor-ß (TGF-ß) isoforms in vascular repair processes. By en face
in situ hybridization, proliferating and quiescent smooth muscle cells
in denuded vessels expressed high levels of mRNA for
TGF-ß1, TGF-ß2, TGF-ß3, and
lower levels of TGF-ß receptor II (TGF-ßRII) mRNA. Compared with
normal endothelium, TGF-ß1 and
TGF-ß2, as well as TGF-ßRII, mRNA were upregulated in
endothelium at the wound edge. Injected recombinant
soluble TGF-ßRII (TGF-ßR:Fc) localized preferentially to the
adventitia and developing neointima in the injured carotid
artery, causing a reduction in intimal lesion formation (up to 65%)
and an increase in lumen area (up to 88%). The gain in lumen area was
largely due to inhibition of negative remodeling, which coincided with
reduced adventitial fibrosis and collagen deposition. Four days after
injury, TGF-ßR:Fc treatment almost completely inhibited the induction
of smooth muscle 
-actin expression in adventitial cells. In the
vessel wall, TGF-ßR:Fc caused a marked reduction in mRNA levels for
collagens type I and III. TGF-ßR:Fc had no effect on
endothelial proliferation as determined by
reendothelialization of the denuded rat aorta.
Together, these findings identify the TGF-ß isoforms as major factors
mediating adventitial fibrosis and negative remodeling after vascular
injury, a major cause of restenosis after angioplasty.
Key Words: intimal hyperplasia • collagen • fibrosis • smooth muscle -actin • myofibroblast
This article has been cited by other articles:
 |
|
 |
|
  A. Giordano, S. Romano, M. Mallardo, A. D'Angelillo, G. Cali, N. Corcione, P. Ferraro, and M. F. Romano FK506 can activate transforming growth factor-{beta} signalling in vascular smooth muscle cells and promote proliferation Cardiovasc Res, August 1, 2008; 79(3): 519 - 526. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. V. Verona, Y. Tang, T. K. Millstead, A. P. Hinck, J. K. Agyin, and L.-Z. Sun Expression, purification and characterization of BGERII: a novel pan-TGF{beta} inhibitor Protein Eng. Des. Sel., July 1, 2008; 21(7): 463 - 473. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Liu, C. Zhang, J. B. Feng, Y. X. Zhao, X. P. Wang, J. M. Yang, M. X. Zhang, X. L. Wang, and Y. Zhang Cross Talk Among Smad, MAPK, and Integrin Signaling Pathways Enhances Adventitial Fibroblast Functions Activated by Transforming Growth Factor-{beta}1 and Inhibited by Gax Arterioscler. Thromb. Vasc. Biol., April 1, 2008; 28(4): 725 - 731. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Fu, M. J. Corbley, L. Sun, J. E. Friedman, F. Shan, J. L. Papadatos, D. Costa, F. Lutterodt, H. Sweigard, S. Bowes, et al. SM16, an Orally Active TGF-{beta} Type I Receptor Inhibitor Prevents Myofibroblast Induction and Vascular Fibrosis in the Rat Carotid Injury Model Arterioscler. Thromb. Vasc. Biol., April 1, 2008; 28(4): 665 - 671. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. S. Horan, S. Wood, V. Ona, D. J. Li, M. E. Lukashev, P. H. Weinreb, K. J. Simon, K. Hahm, N. E. Allaire, N. J. Rinaldi, et al. Partial Inhibition of Integrin {alpha}v 6 Prevents Pulmonary Fibrosis without Exacerbating Inflammation Am. J. Respir. Crit. Care Med., January 1, 2008; 177(1): 56 - 65. [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]
|
|
|
|
|
|
R. Khan, A. Agrotis, and A. Bobik Understanding the role of transforming growth factor-{beta}1 in intimal thickening after vascular injury Cardiovasc Res, May 1, 2007; 74(2): 223 - 234. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. LeClair, T. Durmus, Q. Wang, P. Pyagay, A. Terzic, and V. Lindner Cthrc1 Is a Novel Inhibitor of Transforming Growth Factor-{beta} Signaling and Neointimal Lesion Formation Circ. Res., March 30, 2007; 100(6): 826 - 833. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Russo, E. del Re, D. Brown, and H. Y. Lin Evidence for a Role of Transforming Growth Factor (TGF)-{beta}1 in the Induction of Postglomerular Albuminuria in Diabetic Nephropathy: Amelioration by Soluble TGF-{beta} Type II Receptor Diabetes, February 1, 2007; 56(2): 380 - 388. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Tharp, B. R. Wamhoff, J. R. Turk, and D. K. Bowles Upregulation of intermediate-conductance Ca2+-activated K+ channel (IKCa1) mediates phenotypic modulation of coronary smooth muscle Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2493 - H2503. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 U. Seay, D. Sedding, S. Krick, M. Hecker, W. Seeger, and O. Eickelberg Transforming Growth Factor-{beta}-Dependent Growth Inhibition in Primary Vascular Smooth Muscle Cells Is p38-Dependent J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 1005 - 1012. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Wesselkamper, L. M. Case, L. N. Henning, M. T. Borchers, J. W. Tichelaar, J. M. Mason, N. Dragin, M. Medvedovic, M. A. Sartor, C. R. Tomlinson, et al. Gene Expression Changes during the Development of Acute Lung Injury Role of Transforming Growth Factor {beta} Am. J. Respir. Crit. Care Med., December 1, 2005; 172(11): 1399 - 1411. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P.G. Sluijter, R. E. Verloop, W. P.C. Pulskens, E. Velema, J. M. Grimbergen, P. H. Quax, M.-J. Goumans, G. Pasterkamp, and D. P.V. de Kleijn Involvement of furin-like proprotein convertases in the arterial response to injury Cardiovasc Res, October 1, 2005; 68(1): 136 - 143. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Khurana, M. Simons, J. F. Martin, and I. C. Zachary Role of Angiogenesis in Cardiovascular Disease: A Critical Appraisal Circulation, September 20, 2005; 112(12): 1813 - 1824. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Mallawaarachchi, P. L. Weissberg, and R. C.M. Siow Smad7 Gene Transfer Attenuates Adventitial Cell Migration and Vascular Remodeling After Balloon Injury Arterioscler. Thromb. Vasc. Biol., July 1, 2005; 25(7): 1383 - 1387. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Pyagay, M. Heroult, Q. Wang, W. Lehnert, J. Belden, L. Liaw, R. E. Friesel, and V. Lindner Collagen Triple Helix Repeat Containing 1, a Novel Secreted Protein in Injured and Diseased Arteries, Inhibits Collagen Expression and Promotes Cell Migration Circ. Res., February 4, 2005; 96(2): 261 - 268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Lindner, Q. Wang, B. A. Conley, R. E. Friesel, and C. P.H. Vary Vascular Injury Induces Expression of Periostin: Implications for Vascular Cell Differentiation and Migration Arterioscler. Thromb. Vasc. Biol., January 1, 2005; 25(1): 77 - 83. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Suzuki, V. Kapoor, H.-K. Cheung, L. E. Ling, P. A. DeLong, L. R. Kaiser, and S. M. Albelda Soluble Type II Transforming Growth Factor-{beta} Receptor Inhibits Established Murine Malignant Mesothelioma Tumor Growth by Augmenting Host Antitumor Immunity Clin. Cancer Res., September 1, 2004; 10(17): 5907 - 5918. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. K. Owens, M. S. Kumar, and B. R. Wamhoff Molecular Regulation of Vascular Smooth Muscle Cell Differentiation in Development and Disease Physiol Rev, July 1, 2004; 84(3): 767 - 801. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. A. Conley, R. Koleva, J. D. Smith, D. Kacer, D. Zhang, C. Bernabeu, and C. P. H. Vary Endoglin Controls Cell Migration and Composition of Focal Adhesions: FUNCTION OF THE CYTOSOLIC DOMAIN J. Biol. Chem., June 25, 2004; 279(26): 27440 - 27449. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Pyo, K. K. Jensen, M. T. Wiekowski, D. Manfra, A. Alcami, M. B. Taubman, and S. A. Lira Inhibition of Intimal Hyperplasia in Transgenic Mice Conditionally Expressing the Chemokine-Binding Protein M3 Am. J. Pathol., June 1, 2004; 164(6): 2289 - 2297. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. P. Sokol and W. P. Schiemann Cystatin C Antagonizes Transforming Growth Factor {beta} Signaling in Normal and Cancer Cells Mol. Cancer Res., March 1, 2004; 2(3): 183 - 195. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-M. Li, L. M. Fan, A. Shah, and G. Brooks Targeting {alpha}v{beta}3 and {alpha}5{beta}1 for gene delivery to proliferating VSMCs: synergistic effect of TGF-{beta}1 Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H1123 - H1131. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. P. Denton, B. Zheng, L. A. Evans, X. Shi-wen, V. H. Ong, I. Fisher, K. Lazaridis, D. J. Abraham, C. M. Black, and B. de Crombrugghe Fibroblast-specific Expression of a Kinase-deficient Type II Transforming Growth Factor {beta} (TGF{beta}) Receptor Leads to Paradoxical Activation of TGF{beta} Signaling Pathways with Fibrosis in Transgenic Mice J. Biol. Chem., June 27, 2003; 278(27): 25109 - 25119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Myers, K. J. Harmon, V. Lindner, and L. Liaw Alterations of Arterial Physiology in Osteopontin-Null Mice Arterioscler. Thromb. Vasc. Biol., June 1, 2003; 23(6): 1021 - 1028. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Shao, Z. Shi, P. J. Gotwals, V. E. Koteliansky, J. George, and D. C. Rockey Cell and Molecular Regulation of Endothelin-1 Production during Hepatic Wound Healing Mol. Biol. Cell, June 1, 2003; 14(6): 2327 - 2341. [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]
|
|
|
|
|
|
J. Ibrahim, J. K. Miyashiro, and B. C. Berk Shear Stress Is Differentially Regulated Among Inbred Rat Strains Circ. Res., May 16, 2003; 92(9): 1001 - 1009. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Zhang, H. O. Akman, E. L. P. Smith, J. Zhao, J. E. Murphy-Ullrich, and O. A. Batuman Cellular response to hypoxia involves signaling via Smad proteins Blood, March 15, 2003; 101(6): 2253 - 2260. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Kintscher, C. Lyon, S. Wakino, D. Bruemmer, X. Feng, S. Goetze, K. Graf, A. Moustakas, B. Staels, E. Fleck, et al. PPAR{alpha} Inhibits TGF-{beta}-Induced {beta}5 Integrin Transcription in Vascular Smooth Muscle Cells by Interacting With Smad4 Circ. Res., November 29, 2002; 91 (11): e35 - e44. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Ward, A. Agrotis, P. Kanellakis, J. Hall, G. Jennings, and A. Bobik Tranilast Prevents Activation of Transforming Growth Factor-{beta} System, Leukocyte Accumulation, and Neointimal Growth in Porcine Coronary Arteries After Stenting Arterioscler. Thromb. Vasc. Biol., June 1, 2002; 22(6): 940 - 948. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Lutgens, M. Gijbels, M. Smook, P. Heeringa, P. Gotwals, V. E. Koteliansky, and M. J.A.P. Daemen Transforming Growth Factor-{beta} Mediates Balance Between Inflammation and Fibrosis During Plaque Progression Arterioscler. Thromb. Vasc. Biol., June 1, 2002; 22(6): 975 - 982. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Sheppard Uses of Expression Microarrays in Studies of Pulmonary Fibrosis, Asthma, Acute Lung Injury, and Emphysema : Roger S. Mitchell Lecture Chest, March 1, 2002; 121(2007): 21S - 25S. [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]
|
|
|
|
|
|
H. O. Akman, H. Zhang, M. A. Q. Siddiqui, W. Solomon, E. L. P. Smith, and O. A. Batuman Response to hypoxia involves transforming growth factor-beta 2 and Smad proteins in human endothelial cells Blood, December 1, 2001; 98(12): 3324 - 3331. [Abstract] [Full Text] [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]
|
|
|
|
|
|
E. Lutgens and M. J.A.P. Daemen Transforming Growth Factor-{beta}: A Local or Systemic Mediator of Plaque Stability? Circ. Res., November 9, 2001; 89(10): 853 - 855. [Full Text] [PDF]
|
|
|
|
|
|
G. Paranya, S. Vineberg, E. Dvorin, S. Kaushal, S. J. Roth, E. Rabkin, F. J. Schoen, and J. Bischoff Aortic Valve Endothelial Cells Undergo Transforming Growth Factor-{beta}-Mediated and Non-Transforming Growth Factor-{beta}-Mediated Transdifferentiation in Vitro Am. J. Pathol., October 1, 2001; 159(4): 1335 - 1343. [Abstract] [Full Text]
|
|
|
|
 |
|
 C. G. Lee, R. J. Homer, Z. Zhu, S. Lanone, X. Wang, V. Koteliansky, J. M. Shipley, P. Gotwals, P. Noble, Q. Chen, et al. Interleukin-13 Induces Tissue Fibrosis by Selectively Stimulating and Activating Transforming Growth Factor {beta}1 J. Exp. Med., September 17, 2001; 194(6): 809 - 822. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Negishi, D. Lu, Y.-Q. Zhang, Y. Sawada, T. Sasaki, T. Kayo, J. Ando, T. Izumi, M. Kurabayashi, I. Kojima, et al. Upregulatory Expression of Furin and Transforming Growth Factor-{beta} by Fluid Shear Stress in Vascular Endothelial Cells Arterioscler. Thromb. Vasc. Biol., May 1, 2001; 21(5): 785 - 790. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Durante, L. Liao, S. V. Reyna, K. J. Peyton, and A. I. Schafer Transforming Growth Factor-{beta}1 Stimulates L-Arginine Transport and Metabolism in Vascular Smooth Muscle Cells : Role in Polyamine and Collagen Synthesis Circulation, February 27, 2001; 103(8): 1121 - 1127. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Ward, P. S. Tsao, A. Agrotis, R. J. Dilley, G. L. Jennings, and A. Bobik Low Blood Flow After Angioplasty Augments Mechanisms of Restenosis : Inward Vessel Remodeling, Cell Migration, and Activity of Genes Regulating Migration Arterioscler. Thromb. Vasc. Biol., February 1, 2001; 21(2): 208 - 213. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. D. Douillet, V. Velarde, J. T. Christopher, R. K. Mayfield, M. E. Trojanowska, and A. A. Jaffa Mechanisms by which bradykinin promotes fibrosis in vascular smooth muscle cells: role of TGF-beta and MAPK Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2829 - H2837. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sajid, M. Lele, and G. A. Stouffer Autocrine thrombospondin partially mediates TGF-beta 1- induced proliferation of vascular smooth muscle cells Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2159 - H2165. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Cosgrove, K. Rodgers, D. Meehan, C. Miller, K. Bovard, A. Gilroy, H. Gardner, V. Kotelianski, P. Gotwals, A. Amatucci, et al. Integrin {alpha}1{beta}1 and Transforming Growth Factor-{beta}1 Play Distinct Roles in Alport Glomerular Pathogenesis and Serve as Dual Targets for Metabolic Therapy Am. J. Pathol., November 1, 2000; 157(5): 1649 - 1659. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-i. Hayashi, N. Watanabe, K. Nakazawa, J. Suzuki, K. Tsushima, T. Tamatani, S. Sakamoto, and M. Isobe Roles of P-Selectin in Inflammation, Neointimal Formation, and Vascular Remodeling in Balloon-Injured Rat Carotid Arteries Circulation, October 3, 2000; 102(14): 1710 - 1717. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Gallagher, Y. Jin, G. Killough, E. K. Blue, and V. Lindner Alterations in expression of myosin and myosin light chain kinases in response to vascular injury Am J Physiol Cell Physiol, October 1, 2000; 279(4): C1078 - C1087. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Yamamoto, R. Morishita, N. Tomita, T. Shimozato, H. Nakagami, A. Kikuchi, M. Aoki, J. Higaki, Y. Kaneda, and T. Ogihara Ribozyme Oligonucleotides Against Transforming Growth Factor-{beta} Inhibited Neointimal Formation After Vascular Injury in Rat Model : Potential Application of Ribozyme Strategy to Treat Cardiovascular Disease Circulation, September 12, 2000; 102(11): 1308 - 1314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Lutgens, K. B. J. M. Cleutjens, S. Heeneman, V. E. Koteliansky, L. C. Burkly, and M. J. A. P. Daemen Both early and delayed anti-CD40L antibody treatment induces a stable plaque phenotype PNAS, June 20, 2000; 97(13): 7464 - 7469. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Agah, K. S. S. Prasad, R. Linnemann, M. T. Firpo, T. Quertermous, and D. A. Dichek Cardiovascular Overexpression of Transforming Growth Factor-{beta}1 Causes Abnormal Yolk Sac Vasculogenesis and Early Embryonic Death Circ. Res., May 26, 2000; 86(10): 1024 - 1030. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. O. Boluyt and O. H.L. Bing Matrix gene expression and decompensated heart failure: The aged SHR model Cardiovasc Res, May 1, 2000; 46(2): 239 - 249. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Pasterkamp, D. P.V de Kleijn, and C. Borst Arterial remodeling in atherosclerosis, restenosis and after alteration of blood flow: potential mechanisms and clinical implications Cardiovasc Res, March 1, 2000; 45(4): 843 - 852. [Abstract] [Full Text] [PDF]
|
|