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. 1988 Sep;82(3):1134–1143. doi: 10.1172/JCI113671

Platelet-derived growth factor mRNA detection in human atherosclerotic plaques by in situ hybridization.

J N Wilcox 1, K M Smith 1, L T Williams 1, S M Schwartz 1, D Gordon 1
PMCID: PMC303629  PMID: 2843568

Abstract

Platelet-derived growth factor (PDGF) mRNA, and mRNA for its receptor, have been localized to specific cell types within the human atherosclerotic plaque, using in situ hybridization. The predominant cell types found to express PDGF A and B chain mRNA are mesenchymal-appearing intimal cells and endothelial cells, respectively, with little or no expression detected in macrophages. The distribution of PDGF receptor mRNA containing cells was also examined and found to be localized predominantly in the plaque intima.

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Selected References

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  1. Barrett T. B., Benditt E. P. Platelet-derived growth factor gene expression in human atherosclerotic plaques and normal artery wall. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2810–2814. doi: 10.1073/pnas.85.8.2810. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barrett T. B., Benditt E. P. sis (platelet-derived growth factor B chain) gene transcript levels are elevated in human atherosclerotic lesions compared to normal artery. Proc Natl Acad Sci U S A. 1987 Feb;84(4):1099–1103. doi: 10.1073/pnas.84.4.1099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Benditt E. P., Benditt J. M. Evidence for a monoclonal origin of human atherosclerotic plaques. Proc Natl Acad Sci U S A. 1973 Jun;70(6):1753–1756. doi: 10.1073/pnas.70.6.1753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Benditt E. P., Gown A. M. Atheroma: the artery wall and the environment. Int Rev Exp Pathol. 1980;21:55–118. [PubMed] [Google Scholar]
  5. Berk B. C., Alexander R. W., Brock T. A., Gimbrone M. A., Jr, Webb R. C. Vasoconstriction: a new activity for platelet-derived growth factor. Science. 1986 Apr 4;232(4746):87–90. doi: 10.1126/science.3485309. [DOI] [PubMed] [Google Scholar]
  6. Betsholtz C., Johnsson A., Heldin C. H., Westermark B., Lind P., Urdea M. S., Eddy R., Shows T. B., Philpott K., Mellor A. L. cDNA sequence and chromosomal localization of human platelet-derived growth factor A-chain and its expression in tumour cell lines. Nature. 1986 Apr 24;320(6064):695–699. doi: 10.1038/320695a0. [DOI] [PubMed] [Google Scholar]
  7. Clowes A. W., Clowes M. M., Reidy M. A. Kinetics of cellular proliferation after arterial injury. III. Endothelial and smooth muscle growth in chronically denuded vessels. Lab Invest. 1986 Mar;54(3):295–303. [PubMed] [Google Scholar]
  8. 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]
  9. Coffey R. J., Jr, Derynck R., Wilcox J. N., Bringman T. S., Goustin A. S., Moses H. L., Pittelkow M. R. Production and auto-induction of transforming growth factor-alpha in human keratinocytes. 1987 Aug 27-Sep 2Nature. 328(6133):817–820. doi: 10.1038/328817a0. [DOI] [PubMed] [Google Scholar]
  10. Cox K. H., DeLeon D. V., Angerer L. M., Angerer R. C. Detection of mrnas in sea urchin embryos by in situ hybridization using asymmetric RNA probes. Dev Biol. 1984 Feb;101(2):485–502. doi: 10.1016/0012-1606(84)90162-3. [DOI] [PubMed] [Google Scholar]
  11. Derynck R., Roberts A. B., Winkler M. E., Chen E. Y., Goeddel D. V. Human transforming growth factor-alpha: precursor structure and expression in E. coli. Cell. 1984 Aug;38(1):287–297. doi: 10.1016/0092-8674(84)90550-6. [DOI] [PubMed] [Google Scholar]
  12. DiCorleto P. E. Cultured endothelial cells produce multiple growth factors for connective tissue cells. Exp Cell Res. 1984 Jul;153(1):167–172. doi: 10.1016/0014-4827(84)90458-0. [DOI] [PubMed] [Google Scholar]
  13. Doolittle R. F., Hunkapiller M. W., Hood L. E., Devare S. G., Robbins K. C., Aaronson S. A., Antoniades H. N. Simian sarcoma virus onc gene, v-sis, is derived from the gene (or genes) encoding a platelet-derived growth factor. Science. 1983 Jul 15;221(4607):275–277. doi: 10.1126/science.6304883. [DOI] [PubMed] [Google Scholar]
  14. Gajdusek C. M. Release of endothelial cell-derived growth factor (ECDGF) by heparin. J Cell Physiol. 1984 Oct;121(1):13–21. doi: 10.1002/jcp.1041210104. [DOI] [PubMed] [Google Scholar]
  15. Geer J. C. Fine structure of human aortic intimal thickening and fatty streaks. Lab Invest. 1965 Oct;14(10):1764–1783. [PubMed] [Google Scholar]
  16. Gown A. M., Tsukada T., Ross R. Human atherosclerosis. II. Immunocytochemical analysis of the cellular composition of human atherosclerotic lesions. Am J Pathol. 1986 Oct;125(1):191–207. [PMC free article] [PubMed] [Google Scholar]
  17. Grotendorst G. R., Chang T., Seppä H. E., Kleinman H. K., Martin G. R. Platelet-derived growth factor is a chemoattractant for vascular smooth muscle cells. J Cell Physiol. 1982 Nov;113(2):261–266. doi: 10.1002/jcp.1041130213. [DOI] [PubMed] [Google Scholar]
  18. Groves H. M., Kinlough-Rathbone R. L., Richardson M., Moore S., Mustard J. F. Platelet interaction with damaged rabbit aorta. Lab Invest. 1979 Feb;40(2):194–200. [PubMed] [Google Scholar]
  19. Haudenschild C. C., Prescott M. F., Chobanian A. V. Effects of hypertension and its reversal on aortic intima lesions of the rat. Hypertension. 1980 Jan-Feb;2(1):33–44. doi: 10.1161/01.hyp.2.1.33. [DOI] [PubMed] [Google Scholar]
  20. Heldin C. H., Wasteson A., Westermark B. Platelet-derived growth factor. Mol Cell Endocrinol. 1985 Mar;39(3):169–187. doi: 10.1016/0303-7207(85)90061-9. [DOI] [PubMed] [Google Scholar]
  21. Holthöfer H., Virtanen I., Kariniemi A. L., Hormia M., Linder E., Miettinen A. Ulex europaeus I lectin as a marker for vascular endothelium in human tissues. Lab Invest. 1982 Jul;47(1):60–66. [PubMed] [Google Scholar]
  22. Jaye M., McConathy E., Drohan W., Tong B., Deuel T., Maciag T. Modulation of the sis gene transcript during endothelial cell differentiation in vitro. Science. 1985 May 17;228(4701):882–885. doi: 10.1126/science.3890179. [DOI] [PubMed] [Google Scholar]
  23. Johnsson A., Heldin C. H., Westermark B., Wasteson A. Platelet-derived growth factor: identification of constituent polypeptide chains. Biochem Biophys Res Commun. 1982 Jan 15;104(1):66–74. doi: 10.1016/0006-291x(82)91941-6. [DOI] [PubMed] [Google Scholar]
  24. Jonasson L., Holm J., Skalli O., Bondjers G., Hansson G. K. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis. 1986 Mar-Apr;6(2):131–138. doi: 10.1161/01.atv.6.2.131. [DOI] [PubMed] [Google Scholar]
  25. Josephs S. F., Ratner L., Clarke M. F., Westin E. H., Reitz M. S., Wong-Staal F. Transforming potential of human c-sis nucleotide sequences encoding platelet-derived growth factor. Science. 1984 Aug 10;225(4662):636–639. doi: 10.1126/science.6740330. [DOI] [PubMed] [Google Scholar]
  26. Klurfeld D. M. Identification of foam cells in human atherosclerotic lesions as macrophages using monoclonal antibodies. Arch Pathol Lab Med. 1985 May;109(5):445–449. [PubMed] [Google Scholar]
  27. Kocher O., Skalli O., Cerutti D., Gabbiani F., Gabbiani G. Cytoskeletal features of rat aortic cells during development. An electron microscopic, immunohistochemical, and biochemical study. Circ Res. 1985 Jun;56(6):829–838. doi: 10.1161/01.res.56.6.829. [DOI] [PubMed] [Google Scholar]
  28. Limas C., Westrum B., Limas C. J. The evolution of vascular changes in the spontaneously hypertensive rat. Am J Pathol. 1980 Feb;98(2):357–384. [PMC free article] [PubMed] [Google Scholar]
  29. Martin G. M., Sprague C. A. Symposium on in vitro studies related to atherogenesis. Life histories of hyperplastoid cell lines from aorta and skin. Exp Mol Pathol. 1973 Apr;18(2):125–141. doi: 10.1016/0014-4800(73)90012-9. [DOI] [PubMed] [Google Scholar]
  30. Martinet Y., Rom W. N., Grotendorst G. R., Martin G. R., Crystal R. G. Exaggerated spontaneous release of platelet-derived growth factor by alveolar macrophages from patients with idiopathic pulmonary fibrosis. N Engl J Med. 1987 Jul 23;317(4):202–209. doi: 10.1056/NEJM198707233170404. [DOI] [PubMed] [Google Scholar]
  31. Mason A. J., Pitts S. L., Nikolics K., Szonyi E., Wilcox J. N., Seeburg P. H., Stewart T. A. The hypogonadal mouse: reproductive functions restored by gene therapy. Science. 1986 Dec 12;234(4782):1372–1378. doi: 10.1126/science.3097822. [DOI] [PubMed] [Google Scholar]
  32. Melton D. A., Krieg P. A., Rebagliati M. R., Maniatis T., Zinn K., Green M. R. Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter. Nucleic Acids Res. 1984 Sep 25;12(18):7035–7056. doi: 10.1093/nar/12.18.7035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Miettinen M., Holthofer H., Lehto V. P., Miettinen A., Virtanen I. Ulex europaeus I lectin as a marker for tumors derived from endothelial cells. Am J Clin Pathol. 1983 Jan;79(1):32–36. doi: 10.1093/ajcp/79.1.32. [DOI] [PubMed] [Google Scholar]
  34. Mornex J. F., Martinet Y., Yamauchi K., Bitterman P. B., Grotendorst G. R., Chytil-Weir A., Martin G. R., Crystal R. G. Spontaneous expression of the c-sis gene and release of a platelet-derived growth factorlike molecule by human alveolar macrophages. J Clin Invest. 1986 Jul;78(1):61–66. doi: 10.1172/JCI112574. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Mosse P. R., Campbell G. R., Wang Z. L., Campbell J. H. Smooth muscle phenotypic expression in human carotid arteries. I. Comparison of cells from diffuse intimal thickenings adjacent to atheromatous plaques with those of the media. Lab Invest. 1985 Nov;53(5):556–562. [PubMed] [Google Scholar]
  36. Nilsson J., Sjölund M., Palmberg L., Thyberg J., Heldin C. H. Arterial smooth muscle cells in primary culture produce a platelet-derived growth factor-like protein. Proc Natl Acad Sci U S A. 1985 Jul;82(13):4418–4422. doi: 10.1073/pnas.82.13.4418. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Orekhov A. N., Kosykh V. A., Repin V. S., Smirnov V. N. Cell proliferation in normal and atherosclerotic human aorta. I. Flow cytofluorometric determination of cellular deoxyribonucleic acid content. Lab Invest. 1983 Apr;48(4):395–398. [PubMed] [Google Scholar]
  38. Osborn M., Caselitz J., Weber K. Heterogeneity of intermediate filament expression in vascular smooth muscle: a gradient in desmin positive cells from the rat aortic arch to the level of the arteria iliaca communis. Differentiation. 1981;20(3):196–202. doi: 10.1111/j.1432-0436.1981.tb01176.x. [DOI] [PubMed] [Google Scholar]
  39. Owens G. K., Rabinovitch P. S., Schwartz S. M. Smooth muscle cell hypertrophy versus hyperplasia in hypertension. Proc Natl Acad Sci U S A. 1981 Dec;78(12):7759–7763. doi: 10.1073/pnas.78.12.7759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Owens G. K., Schwartz S. M. Alterations in vascular smooth muscle mass in the spontaneously hypertensive rat. Role of cellular hypertrophy, hyperploidy, and hyperplasia. Circ Res. 1982 Sep;51(3):280–289. doi: 10.1161/01.res.51.3.280. [DOI] [PubMed] [Google Scholar]
  41. Rosenthal A., Chan S. Y., Henzel W., Haskell C., Kuang W. J., Chen E., Wilcox J. N., Ullrich A., Goeddel D. V., Routtenberg A. Primary structure and mRNA localization of protein F1, a growth-related protein kinase C substrate associated with synaptic plasticity. EMBO J. 1987 Dec 1;6(12):3641–3646. doi: 10.1002/j.1460-2075.1987.tb02696.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Ross R., Glomset J. A. The pathogenesis of atherosclerosis (first of two parts). N Engl J Med. 1976 Aug 12;295(7):369–377. doi: 10.1056/NEJM197608122950707. [DOI] [PubMed] [Google Scholar]
  43. Ross R., Glomset J. A. The pathogenesis of atherosclerosis (second of two parts). N Engl J Med. 1976 Aug 19;295(8):420–425. doi: 10.1056/NEJM197608192950805. [DOI] [PubMed] [Google Scholar]
  44. Ross R. The pathogenesis of atherosclerosis--an update. N Engl J Med. 1986 Feb 20;314(8):488–500. doi: 10.1056/NEJM198602203140806. [DOI] [PubMed] [Google Scholar]
  45. Ross R., Wight T. N., Strandness E., Thiele B. Human atherosclerosis. I. Cell constitution and characteristics of advanced lesions of the superficial femoral artery. Am J Pathol. 1984 Jan;114(1):79–93. [PMC free article] [PubMed] [Google Scholar]
  46. Schwartz S. M., Campbell G. R., Campbell J. H. Replication of smooth muscle cells in vascular disease. Circ Res. 1986 Apr;58(4):427–444. doi: 10.1161/01.res.58.4.427. [DOI] [PubMed] [Google Scholar]
  47. Seifert R. A., Schwartz S. M., Bowen-Pope D. F. Developmentally regulated production of platelet-derived growth factor-like molecules. Nature. 1984 Oct 18;311(5987):669–671. doi: 10.1038/311669a0. [DOI] [PubMed] [Google Scholar]
  48. Shimokado K., Raines E. W., Madtes D. K., Barrett T. B., Benditt E. P., Ross R. A significant part of macrophage-derived growth factor consists of at least two forms of PDGF. Cell. 1985 Nov;43(1):277–286. doi: 10.1016/0092-8674(85)90033-9. [DOI] [PubMed] [Google Scholar]
  49. Skalli O., Ropraz P., Trzeciak A., Benzonana G., Gillessen D., Gabbiani G. A monoclonal antibody against alpha-smooth muscle actin: a new probe for smooth muscle differentiation. J Cell Biol. 1986 Dec;103(6 Pt 2):2787–2796. doi: 10.1083/jcb.103.6.2787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Spagnoli L. G., Villaschi S., Neri L., Palmieri G., Taurino M., Faraglia V., Fiorani P. Autoradiographic studies of the smooth muscle cells in human arteries. Paroi Arterielle. 1981;7(3):107–112. [PubMed] [Google Scholar]
  51. Starksen N. F., Harsh G. R., 4th, Gibbs V. C., Williams L. T. Regulated expression of the platelet-derived growth factor A chain gene in microvascular endothelial cells. J Biol Chem. 1987 Oct 25;262(30):14381–14384. [PubMed] [Google Scholar]
  52. Swan D. C., McBride O. W., Robbins K. C., Keithley D. A., Reddy E. P., Aaronson S. A. Chromosomal mapping of the simian sarcoma virus onc gene analogue in human cells. Proc Natl Acad Sci U S A. 1982 Aug;79(15):4691–4695. doi: 10.1073/pnas.79.15.4691. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Tsukada T., Tippens D., Gordon D., Ross R., Gown A. M. HHF35, a muscle-actin-specific monoclonal antibody. I. Immunocytochemical and biochemical characterization. Am J Pathol. 1987 Jan;126(1):51–60. [PMC free article] [PubMed] [Google Scholar]
  54. Ueyama H., Hamada H., Battula N., Kakunaga T. Structure of a human smooth muscle actin gene (aortic type) with a unique intron site. Mol Cell Biol. 1984 Jun;4(6):1073–1078. doi: 10.1128/mcb.4.6.1073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Verweij C. L., Diergaarde P. J., Hart M., Pannekoek H. Full-length von Willebrand factor (vWF) cDNA encodes a highly repetitive protein considerably larger than the mature vWF subunit. EMBO J. 1986 Aug;5(8):1839–1847. doi: 10.1002/j.1460-2075.1986.tb04435.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Villaschi S., Spagnoli L. G. Autoradiographic and ultrastructural studies on the human fibro-atheromatous plaque. Atherosclerosis. 1983 Jul;48(1):95–100. doi: 10.1016/0021-9150(83)90020-5. [DOI] [PubMed] [Google Scholar]
  57. Walker L. N., Bowen-Pope D. F., Ross R., Reidy M. A. Production of platelet-derived growth factor-like molecules by cultured arterial smooth muscle cells accompanies proliferation after arterial injury. Proc Natl Acad Sci U S A. 1986 Oct;83(19):7311–7315. doi: 10.1073/pnas.83.19.7311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Walker L. N., Reidy M. A., Bowyer D. E. Morphology and cell kinetics of fatty streak lesion formation in the hypercholesterolemic rabbit. Am J Pathol. 1986 Dec;125(3):450–459. [PMC free article] [PubMed] [Google Scholar]
  59. Waterfield M. D., Scrace G. T., Whittle N., Stroobant P., Johnsson A., Wasteson A., Westermark B., Heldin C. H., Huang J. S., Deuel T. F. Platelet-derived growth factor is structurally related to the putative transforming protein p28sis of simian sarcoma virus. Nature. 1983 Jul 7;304(5921):35–39. doi: 10.1038/304035a0. [DOI] [PubMed] [Google Scholar]
  60. Wilcox J. N., Derynck R. Localization of cells synthesizing transforming growth factor-alpha mRNA in the mouse brain. J Neurosci. 1988 Jun;8(6):1901–1904. doi: 10.1523/JNEUROSCI.08-06-01901.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]

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