Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1994 Mar;93(3):1172–1178. doi: 10.1172/JCI117070

Antibodies against transforming growth factor-beta 1 suppress intimal hyperplasia in a rat model.

Y G Wolf 1, L M Rasmussen 1, E Ruoslahti 1
PMCID: PMC294068  PMID: 8132757

Abstract

Intimal hyperplasia is induced by therapeutic vascular interventions and often results in clinically important narrowing of the vascular lumen. Examination of the role of TGF-beta 1 in a rat carotid artery injury model confirmed the presence of a previously reported increase in TGF-beta 1 mRNA in the media of injured arteries. Administration of neutralizing anti- TGF-beta 1 antibodies significantly (P < 0.05) reduced the size of the intimal lesions that developed after carotid balloon injury. A control antibody had no effect. The intimal/medial area ratio was also reduced in the anti-TGF-beta 1 group relative to controls (P < 0.01). Immunohistochemical staining showed that two TGF-beta 1-induced extracellular matrix components, EDA + fibronectin and versican, were greatly increased in the untreated neointimal lesions, but were almost completely absent from the lesions of the anti-TGF-beta 1-treated animals. We conclude that TGF-beta 1 is causally involved in the development of intimal hyperplasia, and that anti-TGF-beta 1 agents may be useful in achieving at least partial control of this condition.

Full text

PDF
1172

Images in this article

1173Image
on p.1173
1175Image
on p.1175
1175Image
on p.1175
1176Image
on p.1176
1176Image
on p.1176
1176Image
on p.1176
1176Image
on p.1176
1176Image
on p.1176
1176Image
on p.1176
1176Image
on p.1176
1176Image
on p.1176

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Antonelli-Orlidge A., Saunders K. B., Smith S. R., D'Amore P. A. An activated form of transforming growth factor beta is produced by cocultures of endothelial cells and pericytes. Proc Natl Acad Sci U S A. 1989 Jun;86(12):4544–4548. doi: 10.1073/pnas.86.12.4544. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Assoian R. K., Sporn M. B. Type beta transforming growth factor in human platelets: release during platelet degranulation and action on vascular smooth muscle cells. J Cell Biol. 1986 Apr;102(4):1217–1223. doi: 10.1083/jcb.102.4.1217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Balza E., Borsi L., Allemanni G., Zardi L. Transforming growth factor beta regulates the levels of different fibronectin isoforms in normal human cultured fibroblasts. FEBS Lett. 1988 Feb 8;228(1):42–44. doi: 10.1016/0014-5793(88)80580-5. [DOI] [PubMed] [Google Scholar]
  4. Battegay E. J., Raines E. W., Seifert R. A., Bowen-Pope D. F., Ross R. TGF-beta induces bimodal proliferation of connective tissue cells via complex control of an autocrine PDGF loop. Cell. 1990 Nov 2;63(3):515–524. doi: 10.1016/0092-8674(90)90448-n. [DOI] [PubMed] [Google Scholar]
  5. Border W. A., Noble N. A., Yamamoto T., Harper J. R., Yamaguchi Y. u., Pierschbacher M. D., Ruoslahti E. Natural inhibitor of transforming growth factor-beta protects against scarring in experimental kidney disease. Nature. 1992 Nov 26;360(6402):361–364. doi: 10.1038/360361a0. [DOI] [PubMed] [Google Scholar]
  6. Border W. A., Okuda S., Languino L. R., Ruoslahti E. Transforming growth factor-beta regulates production of proteoglycans by mesangial cells. Kidney Int. 1990 Feb;37(2):689–695. doi: 10.1038/ki.1990.35. [DOI] [PubMed] [Google Scholar]
  7. Border W. A., Ruoslahti E. Transforming growth factor-beta in disease: the dark side of tissue repair. J Clin Invest. 1992 Jul;90(1):1–7. doi: 10.1172/JCI115821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Borsi L., Carnemolla B., Castellani P., Rosellini C., Vecchio D., Allemanni G., Chang S. E., Taylor-Papadimitriou J., Pande H., Zardi L. Monoclonal antibodies in the analysis of fibronectin isoforms generated by alternative splicing of mRNA precursors in normal and transformed human cells. J Cell Biol. 1987 Mar;104(3):595–600. doi: 10.1083/jcb.104.3.595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cheifetz S., Weatherbee J. A., Tsang M. L., Anderson J. K., Mole J. E., Lucas R., Massagué J. The transforming growth factor-beta system, a complex pattern of cross-reactive ligands and receptors. Cell. 1987 Feb 13;48(3):409–415. doi: 10.1016/0092-8674(87)90192-9. [DOI] [PubMed] [Google Scholar]
  10. Chen J. K., Hoshi H., McKeehan W. L. Transforming growth factor type beta specifically stimulates synthesis of proteoglycan in human adult arterial smooth muscle cells. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5287–5291. doi: 10.1073/pnas.84.15.5287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Clowes A. W., Reidy M. A., Clowes M. M. Kinetics of cellular proliferation after arterial injury. I. Smooth muscle growth in the absence of endothelium. Lab Invest. 1983 Sep;49(3):327–333. [PubMed] [Google Scholar]
  12. Clowes A. W., Reidy M. A., Clowes M. M. Mechanisms of stenosis after arterial injury. Lab Invest. 1983 Aug;49(2):208–215. [PubMed] [Google Scholar]
  13. Edelman E. R., Nugent M. A., Smith L. T., Karnovsky M. J. Basic fibroblast growth factor enhances the coupling of intimal hyperplasia and proliferation of vasa vasorum in injured rat arteries. J Clin Invest. 1992 Feb;89(2):465–473. doi: 10.1172/JCI115607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ferns G. A., Raines E. W., Sprugel K. H., Motani A. S., Reidy M. A., Ross R. Inhibition of neointimal smooth muscle accumulation after angioplasty by an antibody to PDGF. Science. 1991 Sep 6;253(5024):1129–1132. doi: 10.1126/science.1653454. [DOI] [PubMed] [Google Scholar]
  15. Gibbons G. H., Pratt R. E., Dzau V. J. Vascular smooth muscle cell hypertrophy vs. hyperplasia. Autocrine transforming growth factor-beta 1 expression determines growth response to angiotensin II. J Clin Invest. 1992 Aug;90(2):456–461. doi: 10.1172/JCI115881. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Glukhova M. A., Frid M. G., Shekhonin B. V., Vasilevskaya T. D., Grunwald J., Saginati M., Koteliansky V. E. Expression of extra domain A fibronectin sequence in vascular smooth muscle cells is phenotype dependent. J Cell Biol. 1989 Jul;109(1):357–366. doi: 10.1083/jcb.109.1.357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hanke H., Haase K. K., Hanke S., Oberhoff M., Hassenstein S., Betz E., Karsch K. R. Morphological changes and smooth muscle cell proliferation after experimental excimer laser treatment. Circulation. 1991 Apr;83(4):1380–1389. doi: 10.1161/01.cir.83.4.1380. [DOI] [PubMed] [Google Scholar]
  18. Heldin C. H. Structural and functional studies on platelet-derived growth factor. EMBO J. 1992 Dec;11(12):4251–4259. doi: 10.1002/j.1460-2075.1992.tb05523.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hessle H., Engvall E. Type VI collagen. Studies on its localization, structure, and biosynthetic form with monoclonal antibodies. J Biol Chem. 1984 Mar 25;259(6):3955–3961. [PubMed] [Google Scholar]
  20. Kähäri V. M., Larjava H., Uitto J. Differential regulation of extracellular matrix proteoglycan (PG) gene expression. Transforming growth factor-beta 1 up-regulates biglycan (PGI), and versican (large fibroblast PG) but down-regulates decorin (PGII) mRNA levels in human fibroblasts in culture. J Biol Chem. 1991 Jun 5;266(16):10608–10615. [PubMed] [Google Scholar]
  21. LeBaron R. G., Zimmermann D. R., Ruoslahti E. Hyaluronate binding properties of versican. J Biol Chem. 1992 May 15;267(14):10003–10010. [PubMed] [Google Scholar]
  22. Lindner V., Lappi D. A., Baird A., Majack R. A., Reidy M. A. Role of basic fibroblast growth factor in vascular lesion formation. Circ Res. 1991 Jan;68(1):106–113. doi: 10.1161/01.res.68.1.106. [DOI] [PubMed] [Google Scholar]
  23. Lindner V., Reidy M. A. Proliferation of smooth muscle cells after vascular injury is inhibited by an antibody against basic fibroblast growth factor. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3739–3743. doi: 10.1073/pnas.88.9.3739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Magnuson V. L., Young M., Schattenberg D. G., Mancini M. A., Chen D. L., Steffensen B., Klebe R. J. The alternative splicing of fibronectin pre-mRNA is altered during aging and in response to growth factors. J Biol Chem. 1991 Aug 5;266(22):14654–14662. [PubMed] [Google Scholar]
  25. Majack R. A. Beta-type transforming growth factor specifies organizational behavior in vascular smooth muscle cell cultures. J Cell Biol. 1987 Jul;105(1):465–471. doi: 10.1083/jcb.105.1.465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Majesky M. W., Lindner V., Twardzik D. R., Schwartz S. M., Reidy M. A. Production of transforming growth factor beta 1 during repair of arterial injury. J Clin Invest. 1991 Sep;88(3):904–910. doi: 10.1172/JCI115393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Majesky M. W., Reidy M. A., Bowen-Pope D. F., Hart C. E., Wilcox J. N., Schwartz S. M. PDGF ligand and receptor gene expression during repair of arterial injury. J Cell Biol. 1990 Nov;111(5 Pt 1):2149–2158. doi: 10.1083/jcb.111.5.2149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Nikol S., Isner J. M., Pickering J. G., Kearney M., Leclerc G., Weir L. Expression of transforming growth factor-beta 1 is increased in human vascular restenosis lesions. J Clin Invest. 1992 Oct;90(4):1582–1592. doi: 10.1172/JCI116027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Noble N. A., Harper J. R., Border W. A. In vivo interactions of TGF-beta and extracellular matrix. Prog Growth Factor Res. 1992;4(4):369–382. doi: 10.1016/0955-2235(92)90017-c. [DOI] [PubMed] [Google Scholar]
  30. 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. 1991 Feb;17(2):433–439. doi: 10.1016/s0735-1097(10)80111-1. [DOI] [PubMed] [Google Scholar]
  31. Ruoslahti E., Hayman E. G., Pierschbacher M., Engvall E. Fibronectin: purification, immunochemical properties, and biological activities. Methods Enzymol. 1982;82(Pt A):803–831. doi: 10.1016/0076-6879(82)82103-4. [DOI] [PubMed] [Google Scholar]
  32. Sato Y., Rifkin D. B. Inhibition of endothelial cell movement by pericytes and smooth muscle cells: activation of a latent transforming growth factor-beta 1-like molecule by plasmin during co-culture. J Cell Biol. 1989 Jul;109(1):309–315. doi: 10.1083/jcb.109.1.309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Sporn M. B., Roberts A. B. Transforming growth factor-beta: recent progress and new challenges. J Cell Biol. 1992 Dec;119(5):1017–1021. doi: 10.1083/jcb.119.5.1017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Zimmermann D. R., Ruoslahti E. Multiple domains of the large fibroblast proteoglycan, versican. EMBO J. 1989 Oct;8(10):2975–2981. doi: 10.1002/j.1460-2075.1989.tb08447.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES