Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Jun 1;97(11):2469–2477. doi: 10.1172/JCI118693

The alpha1beta1 integrin is expressed during neointima formation in rat arteries and mediates collagen matrix reorganization.

P J Gotwals 1, G Chi-Rosso 1, V Lindner 1, J Yang 1, L Ling 1, S E Fawell 1, V E Koteliansky 1
PMCID: PMC507331  PMID: 8647938

Abstract

Remodeling of the extracellular matrix by activated mesenchymal cells (myofibroblasts) is a critical aspect of wound repair in all adult organs. Collagen-dependent gel contraction, a process requiring integrin function, is an established in vitro assay thought to mimic in vivo matrix remodeling. Numerous data have implicated the alpha2beta1 integrin in various cell types as the primary collagen receptor responsible for collagen gel contraction. However, evidence from the literature suggests that the major collagen binding integrin expressed on mesenchymally derived cells in situ is the alpha1beta1 integrin, not the alpha2beta1 integrin. In this report, we use a rat vascular injury model to illustrate that the alpha1beta1 integrin is the major collagen receptor expressed on vascular smooth muscle cells after injury. Using two smooth muscle cell lines, expressing either the alpha1beta1 integrin alone or both the alpha1beta1 and alpha2beta1 integrins, along with Chinese hamster ovary cells transfected with the alpha1 integrin, we demonstrate that alpha1beta1 supports not only collagen-dependent adhesion and migration, but also gel contraction. These data suggest that in vivo the alpha1beta1 integrin is a critical collagen receptor on mesenchymally derived cells potentially involved in matrix remodeling after injury.

Full Text

The Full Text of this article is available as a PDF (446.8 KB).

Selected References

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

  1. Belkin A. M., Klimanskaya I. V., Lukashev M. E., Lilley K., Critchley D. R., Koteliansky V. E. A novel phosphoglucomutase-related protein is concentrated in adherens junctions of muscle and nonmuscle cells. J Cell Sci. 1994 Jan;107(Pt 1):159–173. doi: 10.1242/jcs.107.1.159. [DOI] [PubMed] [Google Scholar]
  2. Belkin A. M., Ornatsky O. I., Kabakov A. E., Glukhova M. A., Koteliansky V. E. Diversity of vinculin/meta-vinculin in human tissues and cultivated cells. Expression of muscle specific variants of vinculin in human aorta smooth muscle cells. J Biol Chem. 1988 May 15;263(14):6631–6635. [PubMed] [Google Scholar]
  3. Belkin V. M., Belkin A. M., Koteliansky V. E. Human smooth muscle VLA-1 integrin: purification, substrate specificity, localization in aorta, and expression during development. J Cell Biol. 1990 Nov;111(5 Pt 1):2159–2170. doi: 10.1083/jcb.111.5.2159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bell E., Ivarsson B., Merrill C. Production of a tissue-like structure by contraction of collagen lattices by human fibroblasts of different proliferative potential in vitro. Proc Natl Acad Sci U S A. 1979 Mar;76(3):1274–1278. doi: 10.1073/pnas.76.3.1274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Carver W., Molano I., Reaves T. A., Borg T. K., Terracio L. Role of the alpha 1 beta 1 integrin complex in collagen gel contraction in vitro by fibroblasts. J Cell Physiol. 1995 Nov;165(2):425–437. doi: 10.1002/jcp.1041650224. [DOI] [PubMed] [Google Scholar]
  6. Chan B. M., Kassner P. D., Schiro J. A., Byers H. R., Kupper T. S., Hemler M. E. Distinct cellular functions mediated by different VLA integrin alpha subunit cytoplasmic domains. Cell. 1992 Mar 20;68(6):1051–1060. doi: 10.1016/0092-8674(92)90077-p. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Duband J. L., Belkin A. M., Syfrig J., Thiery J. P., Koteliansky V. E. Expression of alpha 1 integrin, a laminin-collagen receptor, during myogenesis and neurogenesis in the avian embryo. Development. 1992 Nov;116(3):585–600. doi: 10.1242/dev.116.3.585. [DOI] [PubMed] [Google Scholar]
  9. Eckes B., Mauch C., Hüppe G., Krieg T. Downregulation of collagen synthesis in fibroblasts within three-dimensional collagen lattices involves transcriptional and posttranscriptional mechanisms. FEBS Lett. 1993 Mar 1;318(2):129–133. doi: 10.1016/0014-5793(93)80006-g. [DOI] [PubMed] [Google Scholar]
  10. Frid M. G., Shekhonin B. V., Koteliansky V. E., Glukhova M. A. Phenotypic changes of human smooth muscle cells during development: late expression of heavy caldesmon and calponin. Dev Biol. 1992 Oct;153(2):185–193. doi: 10.1016/0012-1606(92)90104-o. [DOI] [PubMed] [Google Scholar]
  11. Gailit J., Clark R. A. Wound repair in the context of extracellular matrix. Curr Opin Cell Biol. 1994 Oct;6(5):717–725. doi: 10.1016/0955-0674(94)90099-x. [DOI] [PubMed] [Google Scholar]
  12. Grinnell F. Fibroblasts, myofibroblasts, and wound contraction. J Cell Biol. 1994 Feb;124(4):401–404. doi: 10.1083/jcb.124.4.401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gullberg D., Gehlsen K. R., Turner D. C., Ahlén K., Zijenah L. S., Barnes M. J., Rubin K. Analysis of alpha 1 beta 1, alpha 2 beta 1 and alpha 3 beta 1 integrins in cell--collagen interactions: identification of conformation dependent alpha 1 beta 1 binding sites in collagen type I. EMBO J. 1992 Nov;11(11):3865–3873. doi: 10.1002/j.1460-2075.1992.tb05479.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gullberg D., Tingström A., Thuresson A. C., Olsson L., Terracio L., Borg T. K., Rubin K. Beta 1 integrin-mediated collagen gel contraction is stimulated by PDGF. Exp Cell Res. 1990 Feb;186(2):264–272. doi: 10.1016/0014-4827(90)90305-t. [DOI] [PubMed] [Google Scholar]
  15. Harris A. K., Stopak D., Wild P. Fibroblast traction as a mechanism for collagen morphogenesis. Nature. 1981 Mar 19;290(5803):249–251. doi: 10.1038/290249a0. [DOI] [PubMed] [Google Scholar]
  16. Hynes R. O. Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 1992 Apr 3;69(1):11–25. doi: 10.1016/0092-8674(92)90115-s. [DOI] [PubMed] [Google Scholar]
  17. Junger W. G., Cardoza T. A., Liu F. C., Hoyt D. B., Goodwin R. Improved rapid photometric assay for quantitative measurement of PMN migration. J Immunol Methods. 1993 Mar 15;160(1):73–79. doi: 10.1016/0022-1759(93)90010-5. [DOI] [PubMed] [Google Scholar]
  18. Kern A., Eble J., Golbik R., Kühn K. Interaction of type IV collagen with the isolated integrins alpha 1 beta 1 and alpha 2 beta 1. Eur J Biochem. 1993 Jul 1;215(1):151–159. doi: 10.1111/j.1432-1033.1993.tb18017.x. [DOI] [PubMed] [Google Scholar]
  19. Klein C. E., Dressel D., Steinmayer T., Mauch C., Eckes B., Krieg T., Bankert R. B., Weber L. Integrin alpha 2 beta 1 is upregulated in fibroblasts and highly aggressive melanoma cells in three-dimensional collagen lattices and mediates the reorganization of collagen I fibrils. J Cell Biol. 1991 Dec;115(5):1427–1436. doi: 10.1083/jcb.115.5.1427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kupper T. S., Ferguson T. A. A potential pathophysiologic role for alpha 2 beta 1 integrin in human eye diseases involving vitreoretinal traction. FASEB J. 1993 Nov;7(14):1401–1406. doi: 10.1096/fasebj.7.14.8224612. [DOI] [PubMed] [Google Scholar]
  21. Lazard D., Sastre X., Frid M. G., Glukhova M. A., Thiery J. P., Koteliansky V. E. Expression of smooth muscle-specific proteins in myoepithelium and stromal myofibroblasts of normal and malignant human breast tissue. Proc Natl Acad Sci U S A. 1993 Feb 1;90(3):999–1003. doi: 10.1073/pnas.90.3.999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lee R. T., Berditchevski F., Cheng G. C., Hemler M. E. Integrin-mediated collagen matrix reorganization by cultured human vascular smooth muscle cells. Circ Res. 1995 Feb;76(2):209–214. doi: 10.1161/01.res.76.2.209. [DOI] [PubMed] [Google Scholar]
  23. Lemire J. M., Covin C. W., White S., Giachelli C. M., Schwartz S. M. Characterization of cloned aortic smooth muscle cells from young rats. Am J Pathol. 1994 May;144(5):1068–1081. [PMC free article] [PubMed] [Google Scholar]
  24. Lindner V., Giachelli C. M., Schwartz S. M., Reidy M. A. A subpopulation of smooth muscle cells in injured rat arteries expresses platelet-derived growth factor-B chain mRNA. Circ Res. 1995 Jun;76(6):951–957. doi: 10.1161/01.res.76.6.951. [DOI] [PubMed] [Google Scholar]
  25. Lindner V., Reidy M. A. Expression of basic fibroblast growth factor and its receptor by smooth muscle cells and endothelium in injured rat arteries. An en face study. Circ Res. 1993 Sep;73(3):589–595. doi: 10.1161/01.res.73.3.589. [DOI] [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. Mechtersheimer G., Barth T., Quentmeier A., Möller P. Differential expression of beta 1 integrins in nonneoplastic smooth and striated muscle cells and in tumors derived from these cells. Am J Pathol. 1994 Jun;144(6):1172–1182. [PMC free article] [PubMed] [Google Scholar]
  28. Mendrick D. L., Kelly D. M. Temporal expression of VLA-2 and modulation of its ligand specificity by rat glomerular epithelial cells in vitro. Lab Invest. 1993 Dec;69(6):690–702. [PubMed] [Google Scholar]
  29. Mendrick D. L., Kelly D. M., duMont S. S., Sandstrom D. J. Glomerular epithelial and mesangial cells differentially modulate the binding specificities of VLA-1 and VLA-2. Lab Invest. 1995 Mar;72(3):367–375. [PubMed] [Google Scholar]
  30. Michel J. B., De Roux N., Plissonnier D., Anidjar S., Salzmann J. L., Levy B. Pathophysiological role of the vascular smooth muscle cell. J Cardiovasc Pharmacol. 1990;16 (Suppl 1):S4–11. [PubMed] [Google Scholar]
  31. Miettinen M., Castello R., Wayner E., Schwarting R. Distribution of VLA integrins in solid tumors. Emergence of tumor-type-related expression. Patterns in carcinomas and sarcomas. Am J Pathol. 1993 Apr;142(4):1009–1018. [PMC free article] [PubMed] [Google Scholar]
  32. Orlandi A., Ehrlich H. P., Ropraz P., Spagnoli L. G., Gabbiani G. Rat aortic smooth muscle cells isolated from different layers and at different times after endothelial denudation show distinct biological features in vitro. Arterioscler Thromb. 1994 Jun;14(6):982–989. doi: 10.1161/01.atv.14.6.982. [DOI] [PubMed] [Google Scholar]
  33. Owens G. K. Regulation of differentiation of vascular smooth muscle cells. Physiol Rev. 1995 Jul;75(3):487–517. doi: 10.1152/physrev.1995.75.3.487. [DOI] [PubMed] [Google Scholar]
  34. Raghow R. The role of extracellular matrix in postinflammatory wound healing and fibrosis. FASEB J. 1994 Aug;8(11):823–831. doi: 10.1096/fasebj.8.11.8070631. [DOI] [PubMed] [Google Scholar]
  35. Rekhter M. D., Zhang K., Narayanan A. S., Phan S., Schork M. A., Gordon D. Type I collagen gene expression in human atherosclerosis. Localization to specific plaque regions. Am J Pathol. 1993 Dec;143(6):1634–1648. [PMC free article] [PubMed] [Google Scholar]
  36. Rothman A., Kulik T. J., Taubman M. B., Berk B. C., Smith C. W., Nadal-Ginard B. Development and characterization of a cloned rat pulmonary arterial smooth muscle cell line that maintains differentiated properties through multiple subcultures. Circulation. 1992 Dec;86(6):1977–1986. doi: 10.1161/01.cir.86.6.1977. [DOI] [PubMed] [Google Scholar]
  37. Sappino A. P., Schürch W., Gabbiani G. Differentiation repertoire of fibroblastic cells: expression of cytoskeletal proteins as marker of phenotypic modulations. Lab Invest. 1990 Aug;63(2):144–161. [PubMed] [Google Scholar]
  38. Schiro J. A., Chan B. M., Roswit W. T., Kassner P. D., Pentland A. P., Hemler M. E., Eisen A. Z., Kupper T. S. Integrin alpha 2 beta 1 (VLA-2) mediates reorganization and contraction of collagen matrices by human cells. Cell. 1991 Oct 18;67(2):403–410. doi: 10.1016/0092-8674(91)90191-z. [DOI] [PubMed] [Google Scholar]
  39. Schnapp L. M., Breuss J. M., Ramos D. M., Sheppard D., Pytela R. Sequence and tissue distribution of the human integrin alpha 8 subunit: a beta 1-associated alpha subunit expressed in smooth muscle cells. J Cell Sci. 1995 Feb;108(Pt 2):537–544. doi: 10.1242/jcs.108.2.537. [DOI] [PubMed] [Google Scholar]
  40. Schwartz S. M., Benditt E. P. Cell replication in the aortic endothelium: a new method for study of the problem. Lab Invest. 1973 Jun;28(6):699–707. [PubMed] [Google Scholar]
  41. Skinner M. P., Raines E. W., Ross R. Dynamic expression of alpha 1 beta 1 and alpha 2 beta 1 integrin receptors by human vascular smooth muscle cells. Alpha 2 beta 1 integrin is required for chemotaxis across type I collagen-coated membranes. Am J Pathol. 1994 Nov;145(5):1070–1081. [PMC free article] [PubMed] [Google Scholar]
  42. Turner D. C., Flier L. A., Carbonetto S. Identification of a cell-surface protein involved in PC12 cell-substratum adhesion and neurite outgrowth on laminin and collagen. J Neurosci. 1989 Sep;9(9):3287–3296. doi: 10.1523/JNEUROSCI.09-09-03287.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Vandenberg P., Kern A., Ries A., Luckenbill-Edds L., Mann K., Kühn K. Characterization of a type IV collagen major cell binding site with affinity to the alpha 1 beta 1 and the alpha 2 beta 1 integrins. J Cell Biol. 1991 Jun;113(6):1475–1483. doi: 10.1083/jcb.113.6.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Wilcox J. N., Smith K. M., Williams L. T., Schwartz S. M., Gordon D. Platelet-derived growth factor mRNA detection in human atherosclerotic plaques by in situ hybridization. J Clin Invest. 1988 Sep;82(3):1134–1143. doi: 10.1172/JCI113671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Zutter M. M., Santoro S. A. Widespread histologic distribution of the alpha 2 beta 1 integrin cell-surface collagen receptor. Am J Pathol. 1990 Jul;137(1):113–120. [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES