Skip to main content
NCBI home page
The Journal of Cell Biology logoLink to The Journal of Cell Biology
. 1990 Nov 1;111(5):2149–2158. doi: 10.1083/jcb.111.5.2149

PDGF ligand and receptor gene expression during repair of arterial injury

PMCID: PMC2116329  PMID: 2172262

Abstract

Smooth muscle cells (SMC) in rat carotid artery leave the quiescent state and proliferate after balloon catheter injury, but the signals for mitogenesis are not known. In this study, the possibility that cells within damaged arteries produce a growth factor that could act locally to stimulate SMC replication and repair was examined. We found that the genes for PDGF-A and -B (ligand) and PDGF receptor (alpha and beta subunits) were expressed in normal and injured carotid arteries and were independently regulated during repair of carotid injury. Two phases of PDGF ligand and receptor gene expression were observed: (a) In the early stage, a large decrease in PDGF beta-receptor mRNA levels preceded 10- to 12-fold increases in PDGF-A transcript abundance in the first 6 h after wounding. No change in PDGF alpha-receptor or PDGF-B gene expression was found at these times. (b) In the chronic phase, 2 wk after injury, neointimal tissue had lower levels of PDGF alpha- receptor mRNA (threefold) and higher levels of PDGF beta-receptor mRNA (three- to fivefold) than did restored media. Moreover, in situ hybridization studies identified a subpopulation of neointimal SMC localized at or near the luminal surface with a different pattern of gene expression than the underlying carotid SMC. Luminal SMC were strongly positive for PDGF-A and PDGF beta-receptor transcripts, while showing little or no hybridization for PDGF-B or PDGF alpha-receptor. Immunohistochemical studies showed strongly positive staining for PDGF- A in SMC along the luminal surface. These data show that changes in PDGF ligand and receptor expression occur at specific times and locations in injured carotid artery and suggest that these changes may play a role in regulating arterial wound repair.

Full Text

The Full Text of this article is available as a PDF (5.2 MB).

Selected References

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

  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., Gajdusek C. M., Schwartz S. M., McDougall J. K., Benditt E. P. Expression of the sis gene by endothelial cells in culture and in vivo. Proc Natl Acad Sci U S A. 1984 Nov;81(21):6772–6774. doi: 10.1073/pnas.81.21.6772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. 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]
  4. 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]
  5. Björkerud S., Bondjers G. Arterial repair and atherosclerosis after mechanical injury. 2. Tissue response after induction of a total local necrosis deep longitudinal injury. Atherosclerosis. 1971 Sep-Oct;14(2):259–276. doi: 10.1016/0021-9150(71)90055-4. [DOI] [PubMed] [Google Scholar]
  6. Block L. H., Emmons L. R., Vogt E., Sachinidis A., Vetter W., Hoppe J. Ca2+-channel blockers inhibit the action of recombinant platelet-derived growth factor in vascular smooth muscle cells. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2388–2392. doi: 10.1073/pnas.86.7.2388. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bowen-Pope D. F., Hart C. E., Seifert R. A. Sera and conditioned media contain different isoforms of platelet-derived growth factor (PDGF) which bind to different classes of PDGF receptor. J Biol Chem. 1989 Feb 15;264(5):2502–2508. [PubMed] [Google Scholar]
  8. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  9. Claesson-Welsh L., Eriksson A., Morén A., Severinsson L., Ek B., Ostman A., Betsholtz C., Heldin C. H. cDNA cloning and expression of a human platelet-derived growth factor (PDGF) receptor specific for B-chain-containing PDGF molecules. Mol Cell Biol. 1988 Aug;8(8):3476–3486. doi: 10.1128/mcb.8.8.3476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Clemmons D. R., Van Wyk J. J. Evidence for a functional role of endogenously produced somatomedinlike peptides in the regulation of DNA synthesis in cultured human fibroblasts and porcine smooth muscle cells. J Clin Invest. 1985 Jun;75(6):1914–1918. doi: 10.1172/JCI111906. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. 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]
  12. 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]
  13. Clowes A. W., Schwartz S. M. Significance of quiescent smooth muscle migration in the injured rat carotid artery. Circ Res. 1985 Jan;56(1):139–145. doi: 10.1161/01.res.56.1.139. [DOI] [PubMed] [Google Scholar]
  14. Cochran B. H., Lillquist J. S., Stiles C. D. Post-transcriptional control of protein synthesis in Balb/c-3T3 cells by platelet-derived growth factor and platelet-poor plasma. J Cell Physiol. 1981 Dec;109(3):429–438. doi: 10.1002/jcp.1041090308. [DOI] [PubMed] [Google Scholar]
  15. Collins T., Ginsburg D., Boss J. M., Orkin S. H., Pober J. S. Cultured human endothelial cells express platelet-derived growth factor B chain: cDNA cloning and structural analysis. Nature. 1985 Aug 22;316(6030):748–750. doi: 10.1038/316748a0. [DOI] [PubMed] [Google Scholar]
  16. Curran T., Peters G., Van Beveren C., Teich N. M., Verma I. M. FBJ murine osteosarcoma virus: identification and molecular cloning of biologically active proviral DNA. J Virol. 1982 Nov;44(2):674–682. doi: 10.1128/jvi.44.2.674-682.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Davies P. F., Olesen S. P., Clapham D. E., Morrel E. M., Schoen F. J. Endothelial communication. State of the art lecture. Hypertension. 1988 Jun;11(6 Pt 2):563–572. doi: 10.1161/01.hyp.11.6.563.a. [DOI] [PubMed] [Google Scholar]
  18. DiCorleto P. E., Bowen-Pope D. F. Cultured endothelial cells produce a platelet-derived growth factor-like protein. Proc Natl Acad Sci U S A. 1983 Apr;80(7):1919–1923. doi: 10.1073/pnas.80.7.1919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Fingerle J., Johnson R., Clowes A. W., Majesky M. W., Reidy M. A. Role of platelets in smooth muscle cell proliferation and migration after vascular injury in rat carotid artery. Proc Natl Acad Sci U S A. 1989 Nov;86(21):8412–8416. doi: 10.1073/pnas.86.21.8412. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Gronwald R. G., Grant F. J., Haldeman B. A., Hart C. E., O'Hara P. J., Hagen F. S., Ross R., Bowen-Pope D. F., Murray M. J. Cloning and expression of a cDNA coding for the human platelet-derived growth factor receptor: evidence for more than one receptor class. Proc Natl Acad Sci U S A. 1988 May;85(10):3435–3439. doi: 10.1073/pnas.85.10.3435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Gronwald R. G., Seifert R. A., Bowen-Pope D. F. Differential regulation of expression of two platelet-derived growth factor receptor subunits by transforming growth factor-beta. J Biol Chem. 1989 May 15;264(14):8120–8125. [PubMed] [Google Scholar]
  22. Grotendorst G. R., Seppä H. E., Kleinman H. K., Martin G. R. Attachment of smooth muscle cells to collagen and their migration toward platelet-derived growth factor. Proc Natl Acad Sci U S A. 1981 Jun;78(6):3669–3672. doi: 10.1073/pnas.78.6.3669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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]
  24. Grünwald J., Haudenschild C. C. Intimal injury in vivo activates vascular smooth muscle cell migration and explant outgrowth in vitro. Arteriosclerosis. 1984 May-Jun;4(3):183–188. doi: 10.1161/01.atv.4.3.183. [DOI] [PubMed] [Google Scholar]
  25. Hart C. E., Bailey M., Curtis D. A., Osborn S., Raines E., Ross R., Forstrom J. W. Purification of PDGF-AB and PDGF-BB from human platelet extracts and identification of all three PDGF dimers in human platelets. Biochemistry. 1990 Jan 9;29(1):166–172. doi: 10.1021/bi00453a022. [DOI] [PubMed] [Google Scholar]
  26. Hart C. E., Forstrom J. W., Kelly J. D., Seifert R. A., Smith R. A., Ross R., Murray M. J., Bowen-Pope D. F. Two classes of PDGF receptor recognize different isoforms of PDGF. Science. 1988 Jun 10;240(4858):1529–1531. doi: 10.1126/science.2836952. [DOI] [PubMed] [Google Scholar]
  27. Heldin C. H., Bäckström G., Ostman A., Hammacher A., Rönnstrand L., Rubin K., Nistér M., Westermark B. Binding of different dimeric forms of PDGF to human fibroblasts: evidence for two separate receptor types. EMBO J. 1988 May;7(5):1387–1393. doi: 10.1002/j.1460-2075.1988.tb02955.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Heldin C. H., Ernlund A., Rorsman C., Rönnstrand L. Dimerization of B-type platelet-derived growth factor receptors occurs after ligand binding and is closely associated with receptor kinase activation. J Biol Chem. 1989 May 25;264(15):8905–8912. [PubMed] [Google Scholar]
  29. 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]
  30. Jørgensen L., Grøthe A. G., Groves H. M., Kinlough-Rathbone R. L., Richardson M., Mustard J. F. Sequence of cellular responses in rabbit aortas following one and two injuries with a balloon catheter. Br J Exp Pathol. 1988 Aug;69(4):473–486. [PMC free article] [PubMed] [Google Scholar]
  31. Kazlauskas A., Bowen-Pope D., Seifert R., Hart C. E., Cooper J. A. Different effects of homo- and heterodimers of platelet-derived growth factor A and B chains on human and mouse fibroblasts. EMBO J. 1988 Dec 1;7(12):3727–3735. doi: 10.1002/j.1460-2075.1988.tb03256.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Lee K. H., Bowen-Pope D. F., Reed R. R. Isolation and characterization of the alpha platelet-derived growth factor receptor from rat olfactory epithelium. Mol Cell Biol. 1990 May;10(5):2237–2246. doi: 10.1128/mcb.10.5.2237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Libby P., Salomon R. N., Payne D. D., Schoen F. J., Pober J. S. Functions of vascular wall cells related to development of transplantation-associated coronary arteriosclerosis. Transplant Proc. 1989 Aug;21(4):3677–3684. [PubMed] [Google Scholar]
  34. Majack R. A., Majesky M. W., Goodman L. V. Role of PDGF-A expression in the control of vascular smooth muscle cell growth by transforming growth factor-beta. J Cell Biol. 1990 Jul;111(1):239–247. doi: 10.1083/jcb.111.1.239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Majesky M. W., Benditt E. P., Schwartz S. M. Expression and developmental control of platelet-derived growth factor A-chain and B-chain/Sis genes in rat aortic smooth muscle cells. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1524–1528. doi: 10.1073/pnas.85.5.1524. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Majesky M. W., Daemen M. J., Schwartz S. M. Alpha 1-adrenergic stimulation of platelet-derived growth factor A-chain gene expression in rat aorta. J Biol Chem. 1990 Jan 15;265(2):1082–1088. [PubMed] [Google Scholar]
  37. Majesky M. W., Schwartz S. M., Clowes M. M., Clowes A. W. Heparin regulates smooth muscle S phase entry in the injured rat carotid artery. Circ Res. 1987 Aug;61(2):296–300. doi: 10.1161/01.res.61.2.296. [DOI] [PubMed] [Google Scholar]
  38. 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]
  39. Nistér M., Hammacher A., Mellström K., Siegbahn A., Rönnstrand L., Westermark B., Heldin C. H. A glioma-derived PDGF A chain homodimer has different functional activities from a PDGF AB heterodimer purified from human platelets. Cell. 1988 Mar 25;52(6):791–799. doi: 10.1016/0092-8674(88)90421-7. [DOI] [PubMed] [Google Scholar]
  40. Paulsson Y., Hammacher A., Heldin C. H., Westermark B. Possible positive autocrine feedback in the prereplicative phase of human fibroblasts. Nature. 1987 Aug 20;328(6132):715–717. doi: 10.1038/328715a0. [DOI] [PubMed] [Google Scholar]
  41. Pegg A. E. Recent advances in the biochemistry of polyamines in eukaryotes. Biochem J. 1986 Mar 1;234(2):249–262. doi: 10.1042/bj2340249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Raines E. W., Dower S. K., Ross R. Interleukin-1 mitogenic activity for fibroblasts and smooth muscle cells is due to PDGF-AA. Science. 1989 Jan 20;243(4889):393–396. doi: 10.1126/science.2783498. [DOI] [PubMed] [Google Scholar]
  43. Ratner L., Josephs S. F., Jarrett R., Reitz M. S., Jr, Wong-Staal F. Nucleotide sequence of transforming human c-sis cDNA clones with homology to platelet-derived growth factor. Nucleic Acids Res. 1985 Jul 25;13(14):5007–5018. doi: 10.1093/nar/13.14.5007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Reidy M. A. A reassessment of endothelial injury and arterial lesion formation. Lab Invest. 1985 Nov;53(5):513–520. [PubMed] [Google Scholar]
  45. Rhee C. Y., Herz F., Spaet T. H. Accelerated culture of aortic smooth muscle cells. Thromb Res. 1977 Jul;11(1):90–94. doi: 10.1016/0049-3848(77)90072-x. [DOI] [PubMed] [Google Scholar]
  46. Ross R., Raines E. W., Bowen-Pope D. F. The biology of platelet-derived growth factor. Cell. 1986 Jul 18;46(2):155–169. doi: 10.1016/0092-8674(86)90733-6. [DOI] [PubMed] [Google Scholar]
  47. 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]
  48. Rubin K., Tingström A., Hansson G. K., Larsson E., Rönnstrand L., Klareskog L., Claesson-Welsh L., Heldin C. H., Fellström B., Terracio L. Induction of B-type receptors for platelet-derived growth factor in vascular inflammation: possible implications for development of vascular proliferative lesions. Lancet. 1988 Jun 18;1(8599):1353–1356. doi: 10.1016/s0140-6736(88)92177-0. [DOI] [PubMed] [Google Scholar]
  49. Sadler J. E., Shelton-Inloes B. B., Sorace J. M., Harlan J. M., Titani K., Davie E. W. Cloning and characterization of two cDNAs coding for human von Willebrand factor. Proc Natl Acad Sci U S A. 1985 Oct;82(19):6394–6398. doi: 10.1073/pnas.82.19.6394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Sarzani R., Brecher P., Chobanian A. V. Growth factor expression in aorta of normotensive and hypertensive rats. J Clin Invest. 1989 Apr;83(4):1404–1408. doi: 10.1172/JCI114029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Schwartz S. M., Reidy M. R., Clowes A. Kinetics of atherosclerosis: a stem cell model. Ann N Y Acad Sci. 1985;454:292–304. doi: 10.1111/j.1749-6632.1985.tb11869.x. [DOI] [PubMed] [Google Scholar]
  52. Schwartz S. M., Stemerman M. B., Benditt E. P. The aortic intima. II. Repair of the aortic lining after mechanical denudation. Am J Pathol. 1975 Oct;81(1):15–42. [PMC free article] [PubMed] [Google Scholar]
  53. Seifert R. A., Hart C. E., Phillips P. E., Forstrom J. W., Ross R., Murray M. J., Bowen-Pope D. F. Two different subunits associate to create isoform-specific platelet-derived growth factor receptors. J Biol Chem. 1989 May 25;264(15):8771–8778. [PubMed] [Google Scholar]
  54. 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]
  55. 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]
  56. Spaet T. H., Stemerman M. B., Veith F. J., Lejnieks I. Intimal injury and regrowth in the rabbit aorta; medial smooth muscle cells as a source of neointima. Circ Res. 1975 Jan;36(1):58–70. doi: 10.1161/01.res.36.1.58. [DOI] [PubMed] [Google Scholar]
  57. Stemerman M. B., Ross R. Experimental arteriosclerosis. I. Fibrous plaque formation in primates, an electron microscope study. J Exp Med. 1972 Oct 1;136(4):769–789. doi: 10.1084/jem.136.4.769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Stimac E., Groppi V. E., Jr, Coffino P. Inhibition of protein synthesis stabilizes histone mRNA. Mol Cell Biol. 1984 Oct;4(10):2082–2090. doi: 10.1128/mcb.4.10.2082. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Terracio L., Rönnstrand L., Tingström A., Rubin K., Claesson-Welsh L., Funa K., Heldin C. H. Induction of platelet-derived growth factor receptor expression in smooth muscle cells and fibroblasts upon tissue culturing. J Cell Biol. 1988 Nov;107(5):1947–1957. doi: 10.1083/jcb.107.5.1947. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. 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]
  61. 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]
  62. Williams L. T. Signal transduction by the platelet-derived growth factor receptor. Science. 1989 Mar 24;243(4898):1564–1570. doi: 10.1126/science.2538922. [DOI] [PubMed] [Google Scholar]
  63. Yarden Y., Escobedo J. A., Kuang W. J., Yang-Feng T. L., Daniel T. O., Tremble P. M., Chen E. Y., Ando M. E., Harkins R. N., Francke U. Structure of the receptor for platelet-derived growth factor helps define a family of closely related growth factor receptors. Nature. 1986 Sep 18;323(6085):226–232. doi: 10.1038/323226a0. [DOI] [PubMed] [Google Scholar]
  64. Zerwes H. G., Risau W. Polarized secretion of a platelet-derived growth factor-like chemotactic factor by endothelial cells in vitro. J Cell Biol. 1987 Nov;105(5):2037–2041. doi: 10.1083/jcb.105.5.2037. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Cell Biology are provided here courtesy of The Rockefeller University Press

RESOURCES