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. 1993 Dec;143(6):1634–1648.

Type I collagen gene expression in human atherosclerosis. Localization to specific plaque regions.

M D Rekhter 1, K Zhang 1, A S Narayanan 1, S Phan 1, M A Schork 1, D Gordon 1
PMCID: PMC1887272  PMID: 7504887

Abstract

Because collagen is a major component of the human atherosclerotic plaque, factors controlling collagen synthesis may have a profound influence on the volume growth of these intimal lesions. In human arteries, we compared normal vs atherosclerotic media vs intimas for type I collagen gene expression using immunocytochemistry and in situ messenger RNA hybridization with subsequent correlations with plaque topographical features. We also determined the associations of such collagen gene expression with proximity to monocyte/macrophages and T lymphocytes. Type I collagen synthesis appears to be upregulated in atherosclerotic plaques compared with their underlying medias and normal internal mammary arteries and coronary diffuse intimal thickenings. At least in established and advanced coronary and carotid plaques, type I collagen gene expression is focal and especially prevalent in fibrous cap and vascularized regions. Although macrophages and type I procollagen messenger RNA and protein are both found in atherosclerotic plaques, no apparent spatial correlation between macrophage presence and type I procollagen presence was found within these atherosclerotic intimas. Type I procollagen presence appears to be negatively associated with the spatial presence of T cells. Thus, human atherosclerotic plaques exhibit nonuniform patterns of type I collagen gene expression. Although the biochemical determinants of this focal gene expression have yet to be determined, it is conceivable that stimulatory/inhibitory cytokines and other factors (eg hemodynamics) play important roles in determining the focal nature of collagen synthesis in atherosclerosis.

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Selected References

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  1. Amento E. P., Ehsani N., Palmer H., Libby P. Cytokines and growth factors positively and negatively regulate interstitial collagen gene expression in human vascular smooth muscle cells. Arterioscler Thromb. 1991 Sep-Oct;11(5):1223–1230. doi: 10.1161/01.atv.11.5.1223. [DOI] [PubMed] [Google Scholar]
  2. Ang A. H., Tachas G., Campbell J. H., Bateman J. F., Campbell G. R. Collagen synthesis by cultured rabbit aortic smooth-muscle cells. Alteration with phenotype. Biochem J. 1990 Jan 15;265(2):461–469. doi: 10.1042/bj2650461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barger A. C., Beeuwkes R., 3rd, Lainey L. L., Silverman K. J. Hypothesis: vasa vasorum and neovascularization of human coronary arteries. A possible role in the pathophysiology of atherosclerosis. N Engl J Med. 1984 Jan 19;310(3):175–177. doi: 10.1056/NEJM198401193100307. [DOI] [PubMed] [Google Scholar]
  4. Barnes M. J. Collagens in atherosclerosis. Coll Relat Res. 1985 Jan;5(1):65–97. doi: 10.1016/s0174-173x(85)80048-0. [DOI] [PubMed] [Google Scholar]
  5. Bornstein P., Sage H. Regulation of collagen gene expression. Prog Nucleic Acid Res Mol Biol. 1989;37:67–106. doi: 10.1016/s0079-6603(08)60695-9. [DOI] [PubMed] [Google Scholar]
  6. Botney M. D., Kaiser L. R., Cooper J. D., Mecham R. P., Parghi D., Roby J., Parks W. C. Extracellular matrix protein gene expression in atherosclerotic hypertensive pulmonary arteries. Am J Pathol. 1992 Feb;140(2):357–364. [PMC free article] [PubMed] [Google Scholar]
  7. Chu M. L., Myers J. C., Bernard M. P., Ding J. F., Ramirez F. Cloning and characterization of five overlapping cDNAs specific for the human pro alpha 1(I) collagen chain. Nucleic Acids Res. 1982 Oct 11;10(19):5925–5934. doi: 10.1093/nar/10.19.5925. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Crouch E. C., Parks W. C., Rosenbaum J. L., Chang D., Whitehouse L., Wu L. J., Stenmark K. R., Orton E. C., Mecham R. P. Regulation of collagen production by medial smooth muscle cells in hypoxic pulmonary hypertension. Am Rev Respir Dis. 1989 Oct;140(4):1045–1051. doi: 10.1164/ajrccm/140.4.1045. [DOI] [PubMed] [Google Scholar]
  9. Eisenstein R. Angiogenesis in arteries: review. Pharmacol Ther. 1991;49(1-2):1–19. doi: 10.1016/0163-7258(91)90019-i. [DOI] [PubMed] [Google Scholar]
  10. Fischer G. M., Swain M. L., Cherian K. Increased vascular collagen and elastin synthesis in experimental atherosclerosis in the rabbit. Variation in synthesis among major vessels. Atherosclerosis. 1980 Jan;35(1):11–20. doi: 10.1016/0021-9150(80)90023-4. [DOI] [PubMed] [Google Scholar]
  11. Foellmer H. G., Kawahara K., Madri J. A., Furthmayr H., Timpl R., Tuderman L. A monoclonal antibody specific for the amino terminal cleavage site of procollagen type I. Eur J Biochem. 1983 Jul 15;134(1):183–189. doi: 10.1111/j.1432-1033.1983.tb07549.x. [DOI] [PubMed] [Google Scholar]
  12. Friedman M. The coronary thrombus: its origin and fate. Hum Pathol. 1971 Mar;2(1):81–128. doi: 10.1016/s0046-8177(71)80022-9. [DOI] [PubMed] [Google Scholar]
  13. Hansson G. K., Holm J., Holm S., Fotev Z., Hedrich H. J., Fingerle J. T lymphocytes inhibit the vascular response to injury. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10530–10534. doi: 10.1073/pnas.88.23.10530. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hansson G. K., Holm J., Jonasson L. Detection of activated T lymphocytes in the human atherosclerotic plaque. Am J Pathol. 1989 Jul;135(1):169–175. [PMC free article] [PubMed] [Google Scholar]
  15. Hansson G. K., Jonasson L., Holm J., Clowes M. M., Clowes A. W. Gamma-interferon regulates vascular smooth muscle proliferation and Ia antigen expression in vivo and in vitro. Circ Res. 1988 Oct;63(4):712–719. doi: 10.1161/01.res.63.4.712. [DOI] [PubMed] [Google Scholar]
  16. Jaeger E., Rust S., Roessner A., Kleinhans G., Buchholz B., Althaus M., Rauterberg J., Gerlach U. Joint occurrence of collagen mRNA containing cells and macrophages in human atherosclerotic vessels. Atherosclerosis. 1991 Jan;86(1):55–68. doi: 10.1016/0021-9150(91)90099-o. [DOI] [PubMed] [Google Scholar]
  17. Jaeger E., Rust S., Scharffetter K., Roessner A., Winter J., Buchholz B., Althaus M., Rauterberg J. Localization of cytoplasmic collagen mRNA in human aortic coarctation: mRNA enhancement in high blood pressure-induced intimal and medial thickening. J Histochem Cytochem. 1990 Sep;38(9):1365–1375. doi: 10.1177/38.9.2387988. [DOI] [PubMed] [Google Scholar]
  18. Jonasson L., Holm J., Hansson G. K. Smooth muscle cells express Ia antigens during arterial response to injury. Lab Invest. 1988 Mar;58(3):310–315. [PubMed] [Google Scholar]
  19. Katsuda S., Okada Y., Minamoto T., Oda Y., Matsui Y., Nakanishi I. Collagens in human atherosclerosis. Immunohistochemical analysis using collagen type-specific antibodies. Arterioscler Thromb. 1992 Apr;12(4):494–502. doi: 10.1161/01.atv.12.4.494. [DOI] [PubMed] [Google Scholar]
  20. Langner R. O., Modrak J. B. Alteration of collagen synthesis in different tissues of the atherosclerotic rabbit. Artery. 1981;9(4):253–261. [PubMed] [Google Scholar]
  21. Lloyd R. V., Cano M., Landefeld T. D. The effects of estrogens on tumor growth and on prolactin and growth hormone mRNA expression in rat pituitary tissues. Am J Pathol. 1988 Nov;133(2):397–406. [PMC free article] [PubMed] [Google Scholar]
  22. 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]
  23. Mayne R. Collagenous proteins of blood vessels. Arteriosclerosis. 1986 Nov-Dec;6(6):585–593. doi: 10.1161/01.atv.6.6.585. [DOI] [PubMed] [Google Scholar]
  24. McCullagh K. G., Ehrhart L. A. Increased arterial collagen synthesis in experimental canine atherosclerosis. Atherosclerosis. 1974 Jan-Feb;19(1):13–28. doi: 10.1016/0021-9150(74)90040-9. [DOI] [PubMed] [Google Scholar]
  25. Mecham R. P., Whitehouse L. A., Wrenn D. S., Parks W. C., Griffin G. L., Senior R. M., Crouch E. C., Stenmark K. R., Voelkel N. F. Smooth muscle-mediated connective tissue remodeling in pulmonary hypertension. Science. 1987 Jul 24;237(4813):423–426. doi: 10.1126/science.3603030. [DOI] [PubMed] [Google Scholar]
  26. Okada Y., Katsuda S., Matsui Y., Watanabe H., Nakanishi I. Collagen synthesis by cultured arterial smooth muscle cells during spontaneous phenotypic modulation. Acta Pathol Jpn. 1990 Mar;40(3):157–164. doi: 10.1111/j.1440-1827.1990.tb03317.x. [DOI] [PubMed] [Google Scholar]
  27. Opsahl W. P., DeLuca D. J., Ehrhart L. A. Accelerated rates of collagen synthesis in atherosclerotic arteries quantified in vivo. Arteriosclerosis. 1987 Sep-Oct;7(5):470–476. doi: 10.1161/01.atv.7.5.470. [DOI] [PubMed] [Google Scholar]
  28. Pierce G. F. Macrophages: important physiologic and pathologic sources of polypeptide growth factors. Am J Respir Cell Mol Biol. 1990 Mar;2(3):233–234. doi: 10.1165/ajrcmb/2.3.233. [DOI] [PubMed] [Google Scholar]
  29. Pietilä K., Nikkari T. Enhanced synthesis of collagen and total protein by smooth muscle cells from atherosclerotic rabbit aortas in culture. Atherosclerosis. 1980 Sep;37(1):11–19. doi: 10.1016/0021-9150(80)90089-1. [DOI] [PubMed] [Google Scholar]
  30. SMITH E. B. THE INFLUENCE OF AGE AND ATHEROSCLEROSIS ON THE CHEMISTRY OF AORTIC INTIMA.2. COLLAGEN AND MUCOPOLYSACCHARIDES. J Atheroscler Res. 1965 Mar-Apr;5(2):241–248. doi: 10.1016/s0368-1319(65)80065-5. [DOI] [PubMed] [Google Scholar]
  31. Sage H., Pritzl P., Bornstein P. Secretory phenotypes of endothelial cells in culture: comparison of aortic, venous, capillary, and corneal endothelium. Arteriosclerosis. 1981 Nov-Dec;1(6):427–442. doi: 10.1161/01.atv.1.6.427. [DOI] [PubMed] [Google Scholar]
  32. Shekhonin B. V., Domogatsky S. P., Muzykantov V. R., Idelson G. L., Rukosuev V. S. Distribution of type I, III, IV and V collagen in normal and atherosclerotic human arterial wall: immunomorphological characteristics. Coll Relat Res. 1985 Sep;5(4):355–368. doi: 10.1016/s0174-173x(85)80024-8. [DOI] [PubMed] [Google Scholar]
  33. Song J. Y., Jin L., Lloyd R. V. Effects of estradiol on prolactin and growth hormone messenger RNAs in cultured normal and neoplastic (MtT/W15 and GH3) rat pituitary cells. Cancer Res. 1989 Mar 1;49(5):1247–1253. [PubMed] [Google Scholar]
  34. Stary H. C. The sequence of cell and matrix changes in atherosclerotic lesions of coronary arteries in the first forty years of life. Eur Heart J. 1990 Aug;11 (Suppl E):3–19. doi: 10.1093/eurheartj/11.suppl_e.3. [DOI] [PubMed] [Google Scholar]
  35. Stavenow L. Differences in bovine aortic smooth muscle cells cultured from spontaneous atherosclerotic lesions of different severity within the same vessel. Atherosclerosis. 1984 Dec;53(3):337–342. doi: 10.1016/0021-9150(84)90135-7. [DOI] [PubMed] [Google Scholar]
  36. Sumpio B. E., Banes A. J., Link W. G., Johnson G., Jr Enhanced collagen production by smooth muscle cells during repetitive mechanical stretching. Arch Surg. 1988 Oct;123(10):1233–1236. doi: 10.1001/archsurg.1988.01400340059010. [DOI] [PubMed] [Google Scholar]
  37. 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]
  38. Zamir M., Silver M. D. Vasculature in the walls of human coronary arteries. Arch Pathol Lab Med. 1985 Jul;109(7):659–662. [PubMed] [Google Scholar]
  39. Zhang K., Kulig E., Jin L., Lloyd R. V. Effects of estrogen and epidermal growth factor on prolactin and Pit-1 mRNA in GH3 cells. Proc Soc Exp Biol Med. 1993 Feb;202(2):193–200. doi: 10.3181/00379727-202-43526. [DOI] [PubMed] [Google Scholar]
  40. van der Wal A. C., Das P. K., Tigges A. J., Becker A. E. Macrophage differentiation in atherosclerosis. An in situ immunohistochemical analysis in humans. Am J Pathol. 1992 Jul;141(1):161–168. [PMC free article] [PubMed] [Google Scholar]

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