1887

Abstract

Human cytomegalovirus (HCMV) infection is known to modulate host gene expression and has been linked to the pathogenesis of vasculopathies; however, relevant pathomechanisms are still unclear. It was shown that HCMV infection leads to upregulation of vascular endothelial growth factor (VEGF) expression in human foreskin fibroblasts and coronary artery smooth muscle cells (SMC). Activation of VEGF transcription by HCMV infection was confirmed by transient-expression experiments, which revealed that a short promoter fragment, pLuc135 (−85 to +50), is sufficient for activation. Site-directed mutagenesis of Sp1-recognition sites within this fragment abolished the upregulation of transcription. Functional VEGF protein is released into the culture supernatant of infected SMC. Incubation of endothelial cells with supernatants from HCMV-infected SMC cultures induced upregulation of VEGF receptor-2 expression on endothelial cells, as well as a significant upregulation of DNA synthesis, implicating cell proliferation. The mean incline of DNA synthesis at 48 and 72 h post-infection was 148 and 197 %, respectively. Addition of neutralizing antibodies against VEGF completely abolished this effect. Supernatants from SMC cultures incubated with UV-inactivated virus induced a comparable effect. This virus-induced paracrine effect may represent a molecular mechanism for HCMV-induced pathogenesis, such as inflammatory vasculopathies, by inducing a proatherogenic phenotype in SMC.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.80327-0
2005-01-01
2024-12-14
Loading full text...

Full text loading...

/deliver/fulltext/jgv/86/1/vir860023.html?itemId=/content/journal/jgv/10.1099/vir.0.80327-0&mimeType=html&fmt=ahah

References

  1. Almeida G. D., Porada C. D., St Jeor S., Ascensao J. L. 1994; Human cytomegalovirus alters interleukin-6 production by endothelial cells. Blood 83:370–376
    [Google Scholar]
  2. Barleon B., Sozzani S., Zhou D., Weich H. A., Mantovani A., Marmé D. 1996; Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 87:3336–3343
    [Google Scholar]
  3. Browne E. P., Wing B., Coleman D., Shenk T. 2001; Altered cellular mRNA levels in human cytomegalovirus-infected fibroblasts: viral block to the accumulation of antiviral mRNAs. J Virol 75:12319–12330 [CrossRef]
    [Google Scholar]
  4. Celletti F. L., Waugh J. M., Amabile P. G., Brendolan A., Hilfiker P. R., Dake M. D. 2001; Vascular endothelial growth factor enhances atherosclerotic plaque progression. Nat Med 7:425–429 [CrossRef]
    [Google Scholar]
  5. Chen Y.-X., Nakashima Y., Tanaka K., Shiraishi S., Nakagawa K., Sueishi K. 1999; Immunohistochemical expression of vascular endothelial growth factor/vascular permeability factor in atherosclerotic intimas of human coronary arteries. Arterioscler Thromb Vasc Biol 19:131–139 [CrossRef]
    [Google Scholar]
  6. Clauss M., Gerlach M., Gerlach H. 7 other authors 1990; Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration. J Exp Med 172:1535–1545 [CrossRef]
    [Google Scholar]
  7. Couffinhal T., Kearney M., Witzenbichler B., Chen D., Murohara T., Losordo D. W., Symes J., Isner J. M. 1997; Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) in normal and atherosclerotic human arteries. Am J Pathol 150:1673–1685
    [Google Scholar]
  8. de Boer O. J., van der Wal A. C., Teeling P., Becker A. E. 1999; Leucocyte recruitment in rupture prone regions of lipid-rich plaques: a prominent role for neovascularization?. Cardiovasc Res 41:443–449 [CrossRef]
    [Google Scholar]
  9. Finkenzeller G., Sparacio A., Technau A., Marmé D., Siemeister G. 1997; Sp1 recognition sites in the proximal promoter of the human vascular endothelial growth factor gene are essential for platelet-derived growth factor-induced gene expression. Oncogene 15:669–676 [CrossRef]
    [Google Scholar]
  10. Hendrix M. G., Daemen M., Bruggeman C. A. 1991; Cytomegalovirus nucleic acid distribution within the human vascular tree. Am J Pathol 138:563–567
    [Google Scholar]
  11. Inoue M., Itoh H., Ueda M. 13 other authors 1998; Vascular endothelial growth factor (VEGF) expression in human coronary atherosclerotic lesions: possible pathophysiological significance of VEGF in progression of atherosclerosis. Circulation 98:2108–2116 [CrossRef]
    [Google Scholar]
  12. Keck P. J., Hauser S. D., Krivi G., Sanzo K., Warren T., Feder J., Connolly D. T. 1989; Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 246:1309–1312 [CrossRef]
    [Google Scholar]
  13. Lemström K. B., Krebs R., Nykänen A. I. 8 other authors 2002; Vascular endothelial growth factor enhances cardiac allograft arteriosclerosis. Circulation 105:2524–2530 [CrossRef]
    [Google Scholar]
  14. Liu C., Okruzhnov Y., Li H., Nicholas J. 2001; Human herpesvirus 8 (HHV-8)-encoded cytokines induce expression of and autocrine signaling by vascular endothelial growth factor (VEGF) in HHV-8-infected primary-effusion lymphoma cell lines and mediate VEGF-independent antiapoptotic effects. J Virol 75:10933–10940 [CrossRef]
    [Google Scholar]
  15. Melnick J. L., Petrie B. L., Dreesman G. R., Burck J., McCollum C. H., DeBakey M. E. 1983; Cytomegalovirus antigen within human arterial smooth muscle cells. Lancet ii:644–647
    [Google Scholar]
  16. Michel D., Pavić I., Zimmermann A., Haupt E., Wunderlich K., Heuschmid M., Mertens T. 1996; The UL97 gene product of human cytomegalovirus is an early-late protein with a nuclear localization but is not a nucleoside kinase. J Virol 70:6340–6347
    [Google Scholar]
  17. Minisini R., Tulone C., Lüske A., Michel D., Mertens T., Gierschik P., Moepps B. 2003; Constitutive inositol phosphate formation in cytomegalovirus-infected human fibroblasts is due to expression of the chemokine receptor homologue pUS28. J Virol 77:4489–4501 [CrossRef]
    [Google Scholar]
  18. Moulton K. S., Heller E., Konerding M. A., Flynn E., Palinski W., Folkman J. 1999; Angiogenesis inhibitors endostatin or TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein E-deficient mice. Circulation 99:1726–1732 [CrossRef]
    [Google Scholar]
  19. Moulton K. S., Vakili K., Zurakowski D. 7 other authors 2003; Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis. Proc Natl Acad Sci U S A 100:4736–4741 [CrossRef]
    [Google Scholar]
  20. Murayama T., Ohara Y., Obuchi M., Khabar K. S. A., Higashi H., Mukaida N., Matsushima K. 1997; Human cytomegalovirus induces interleukin-8 production by a human monocytic cell line, THP-1, through acting concurrently on AP-1- and NF- κ B-binding sites of the interleukin-8 gene. J Virol 71:5692–5695
    [Google Scholar]
  21. Reinhardt B., Minisini R., Mertens T. 2002; Opinion article: cytomegalovirus is a risk factor in atherogenesis. Herpes 9:21–23
    [Google Scholar]
  22. Reinhardt B., Vaida B., Voisard R. 7 other authors 2003; Human cytomegalovirus infection in human renal arteries in vitro. J Virol Methods 109:1–9 [CrossRef]
    [Google Scholar]
  23. Sambrook J., Fritsch E. F., Maniatis T. 1989 Molecular Cloning: a Laboratory Manual , 2nd edn. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory;
    [Google Scholar]
  24. Sedmak D. D., Knight D. A., Vook N. C., Waldman J. W. 1994; Divergent patterns of ELAM-1, ICAM-1, and VCAM-1 expression on cytomegalovirus-infected endothelial cells. Transplantation 58:1379–1385
    [Google Scholar]
  25. Speir E., Modali R., Huang E. S., Leon M. B., Shawl F., Finkel T., Epstein S. E. 1994; Potential role of human cytomegalovirus and p53 interaction in coronary restenosis. Science 265:391–394 [CrossRef]
    [Google Scholar]
  26. Srivastava R., Curtis M., Hendrickson S., Burns W. H., Hosenpud J. D. 1999; Strain specific effects of cytomegalovirus on endothelial cells: implications for investigating the relationship between CMV and cardiac allograft vasculopathy. Transplantation 68:1568–1573 [CrossRef]
    [Google Scholar]
  27. Streblow D. N., Soderberg-Naucler C., Vieira J., Smith P., Wakabayashi E., Ruchti F., Mattison K., Altschuler Y., Nelson J. A. 1999; The human cytomegalovirus chemokine receptor US28 mediates vascular smooth muscle cell migration. Cell 99:511–520 [CrossRef]
    [Google Scholar]
  28. Waltenberger J. 1997; Modulation of growth factor action: implications for the treatment of cardiovascular diseases. Circulation 96:4083–4094 [CrossRef]
    [Google Scholar]
  29. Zachary I., Gliki G. 2001; Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family. Cardiovasc Res 49:568–581 [CrossRef]
    [Google Scholar]
  30. Zheng M., Deshpande S., Lee S., Ferrara N., Rouse B. T. 2001; Contribution of vascular endothelial growth factor in the neovascularization process during the pathogenesis of herpetic stromal keratitis. J Virol 75:9828–9835 [CrossRef]
    [Google Scholar]
  31. Zhou Y. F., Leon M. B., Waclawiw M. A., Popma J. J., Yu Z. X., Finkel T., Epstein S. E. 1996; Association between prior cytomegalovirus infection and the risk of restenosis after coronary atherectomy. N Engl J Med 335:624–630 [CrossRef]
    [Google Scholar]
  32. Zhu H., Cong J.-P., Mamtora G., Gingeras T., Shenk T. 1998; Cellular gene expression altered by human cytomegalovirus: global monitoring with oligonucleotide arrays. Proc Natl Acad Sci U S A 95:14470–14475 [CrossRef]
    [Google Scholar]
/content/journal/jgv/10.1099/vir.0.80327-0
Loading
/content/journal/jgv/10.1099/vir.0.80327-0
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error