Mechanisms of Cytomegalovirus-Accelerated Vascular Disease: Induction of Paracrine Factors That Promote Angiogenesis and Wound Healing

  • D. N. Streblow
  • J. Dumortier
  • A. V. Moses
  • S. L. Orloff
  • J. A. Nelson
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 325)

Human cytomegalovirus (HCMV) is associated with the acceleration of a number of vascular diseases such as atherosclerosis, restenosis, and transplant vascular sclerosis (TVS). All of these diseases are the result of either mechanical or immunemediated injury followed by inflammation and subsequent smooth muscle cell (SMC) migration from the vessel media to the intima and proliferation that culminates in vessel narrowing. A number of epidemiological and animal studies have demonstrated that CMV significantly accelerates TVS and chronic rejection (CR) in solid organ allografts. In addition, treatment of human recipients and animals alike with the antiviral drug ganciclovir results in prolonged survival of the allograft, indicating that CMV replication is a requirement for acceleration of disease. However, although virus persists in the allograft throughout the course of disease, the number of directly infected cells does not account for the global effects that the virus has on the acceleration of TVS and CR. Recent investigations of up- and downregulated cellular genes in infected allografts in comparison to native heart has demonstrated that rat CMV (RCMV) upregulates genes involved in wound healing (WH) and angiogenesis (AG). Consistent with this result, we have found that supernatants from HCMV-infected cells (HCMV secretome) induce WH and AG using in vitro models. Taken together, these findings suggest that one mechanism for HCMV acceleration of TVS is mediated through induction of secreted cytokines and growth factors from virus-infected cells that promote WH and AG in the allograft, resulting in the acceleration of TVS. We review here the ability of CMV infection to alter the local environment by producing cellular factors that act in a paracrine fashion to enhance WH and AG processes associated with the development of vascular disease, which accelerates chronic allograft rejection.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Almeida GD, Porada CD, St Jeor S, Ascensao JL (1994) Human cytomegalovirus alters interleukin-6 production by endothelial cells. Blood 83:370–376.PubMedGoogle Scholar
  2. Almeida-Porada G, Porada CD, Shanley JD, Ascensao JL (1997) Altered production of GM-CSF and IL-8 in cytomegalovirus-infected, IL-1- primed umbilical cord endothelial cells. Exp Hematol 25:1278–1285.PubMedGoogle Scholar
  3. Auerbach R, Lewis R, Shinners B, Kubai L, Akhtar N (2003) Angiogenesis assays: a critical overview. Clin Chem 49:32–40.PubMedCrossRefGoogle Scholar
  4. Billingham ME (1992) Histopathology of graft coronary disease. J Heart Lung Transplant 11:S38–S44.PubMedGoogle Scholar
  5. Bouis D, Kusumanto Y, Meijer C, Mulder NH, Hospers GA (2006) A review on pro- and anti-angiogenic factors as targets of clinical intervention. Pharmacol Res 53:89–103.PubMedCrossRefGoogle Scholar
  6. Bruning JH, Persoons MCJ, Lemstrom KB, Stals FS, De Clereq E, Bruggeman CA (1994) Enhancement of transplantation associated atherosclerosis by CMV, which can be prevented by antiviral therapy in the form of HPMPC. Transplant Int 7:365–370.CrossRefGoogle Scholar
  7. Burns LJ, Pooley JC, Walsh DJ, Vercellotti GM, Weber ML, Kovacs A (1999) Intercellular adhesion molecule-1 expression in endothelial cells is activated by cytomegalovirus immediate early proteins. Transplantation 67:137–144.PubMedCrossRefGoogle Scholar
  8. Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9:653–660.PubMedCrossRefGoogle Scholar
  9. Charrier L, Yan Y, Driss A, Laboisse CL, Sitaraman SV, Merlin D (2005) ADAM-15 inhibits wound healing in human intestinal epithelial cell monolayers. Am J Physiol Gastrointest Liver Physiol 288:G346–G353.PubMedCrossRefGoogle Scholar
  10. Clinton SK, Libby P (1992) Cytokines and growth factors in atherogenesis. Arch Pathol Lab Med 116:1292.PubMedGoogle Scholar
  11. Deotero J, Gavalda J, Murio E, et al (1998) Cytomegalovirus disease as a risk factor for graft loss and death after orthotopic liver transplantation. Clin Invest Dis 26:865–870.CrossRefGoogle Scholar
  12. Ely JM, Greiner DL, Lubaroff DM, Fitch FW (1983) Characterization of monoclonal antibodies that define rat T cell alloantigens. J Immunol 130:2798.PubMedGoogle Scholar
  13. Fitzgerald JT, Gallay B, Taranto SE, McVicar JP, Troppmann C, Chen X, McIntosh MJ, Perez RV (2004) Pretransplant recipient cytomegalovirus seropositivity and hemodialysis are associated with decreased renal allograft and patient survival. Transplantation 77:1405–1411.PubMedCrossRefGoogle Scholar
  14. Folkman J (2003) Fundamental concepts of the angiogenic process. Curr Mol Med 3:643–651.PubMedCrossRefGoogle Scholar
  15. Grattan MT, Moreno-Cabral CE, Starnes VA, Oyer PE, Stinson EB, Shumway NE (1989) Cytomegalovirus infection is associated with cardiac allograft rejection and atherosclerosis. JAMA 261:3561–3566.PubMedCrossRefGoogle Scholar
  16. Guidolin D, Vacca A, Nussdorfer GG, Ribatti D (2004) A new image analysis method based on topological and fractal parameters to evaluate the angiostatic activity of docetaxel by using the matrigel assay in vitro. Microvasc Res 67:117–124.PubMedCrossRefGoogle Scholar
  17. Helantera I, Loginov R, Koskinen P, Tornroth T, Gronhagen-Riska C, Lautenschlager I (2005) Persistent cytomegalovirus infection is associated with increased expression of TGF-beta1, PDGF-AA and ICAM-1 and arterial intimal thickening in kidney allografts. Nephrol Dial Transplant 20:790–796.PubMedCrossRefGoogle Scholar
  18. Helantera I, Teppo AM, Koskinen P, Tornroth T, Gronhagen-Riska C, Lautenschlager I (2006) Increased urinary excretion of transforming growth factor-beta(1) in renal transplant recipients during cytomegalovirus infection. Transpl Immunol 15:217–221.PubMedCrossRefGoogle Scholar
  19. Hosenpud JD, Shipley GD, Wagner CR (1992) Cardiac allograft vasculopathy: current concepts, recent developments and future directions. J Heart Lung Transplant 11:9–23.PubMedGoogle Scholar
  20. Humar A, St Louis P, Mazzulli T, McGeer A, Lipton J, Messner H, MacDonald KS (1999) Elevated serum cytokines are associated with cytomegalovirus infection and disease in bone marrow transplant recipients. J Infect Dis 179:484–488.PubMedCrossRefGoogle Scholar
  21. Inkinen K, Holma K, Soots A, Krogerus L, Loginov R, Bruggeman C, Ahonen J, Lautenschlager I (2003) Expression of TGF-beta and PDGF-AA antigens and corresponding mRNAs in cytomegalovirus-infected rat kidney allografts. Transplant Proc 35:804–805.PubMedCrossRefGoogle Scholar
  22. Inkinen K, Soots A, Krogerus L, Loginov R, Bruggeman C, Lautenschlager I (2005) Cytomegalovirus enhances expression of growth factors during the development of chronic allograft nephropathy in rats. Transpl Int 18:743–749.PubMedCrossRefGoogle Scholar
  23. Keese CR, Wegener J, Walker SR, Giaever I (2004) Electrical wound-healing assay for cells in vitro. Proc Natl Acad Sci U S A 101:1554–1559.PubMedCrossRefGoogle Scholar
  24. Kent D, Sheridan C (2003) Choroidal neovascularization: a wound healing perspective. Mol Vis 9:747–755.PubMedGoogle Scholar
  25. Khurana R, Simons M (2003) Insights from angiogenesis trials using fibroblast growth factor for advanced arteriosclerotic disease. Trends Cardiovasc Med 13:116–122.PubMedCrossRefGoogle Scholar
  26. Klempnauer J, Marquarding E (1989) RT1.C and rat bone marrow transplantation. Transplant Proc 21:3292.PubMedGoogle Scholar
  27. Lemstrom KB, Bruning JH, Bruggeman CA, Lautenschlager IT, Hayry PJ (1993) Cytomegalovirus infection enhances smooth muscle cell proliferation and intimal thickening of rat aortic allografts. J Clin Invest 92:549–558.PubMedCrossRefGoogle Scholar
  28. Lemstrom K, Koskinen P, Krogerus L, Daemen M, Bruggeman CA, Hayry PJ (1995) Cytomegalovirus antigen expression, endothelial cell proliferation, and intimal thickening in rat cardiac allografts after cytomegalovirus infection. Circulation 92:2594–2604.PubMedGoogle Scholar
  29. Libby P, Salomon RN, Payne DD, Schoen FJ, Pober JS (1989) Functions of vascular wall cells related to development of transplantation-associated coronary arteriosclerosis. Transplant Proc 21:3677–3684.PubMedGoogle Scholar
  30. Lubaroff DM, Rasmussen GT, Hunt HD (1989) The RT6 T cell antigen: its role in the identification of functional subsets and in T cell activation. Transplant Proc 21:3251.PubMedGoogle Scholar
  31. Melnick JL, Petrie BL, Dreesman GR, Burek J, McCollum CH, DeBakey ME (1983) Cytomegalovirus antigen within human arterial smooth muscle cells. Lancet 2:644–647.PubMedCrossRefGoogle Scholar
  32. Melnick JL, Adam E, DeBakey ME (1998) The link between CMV and atherosclerosis. Infect Med 15:479–486.Google Scholar
  33. Merigan TC, Renlund DG, Keay S et al (1992) A controlled trial of ganciclovir to prevent cytomegalovirus disease after heart transplantation. N Engl J Med 326:1182–1186.PubMedGoogle Scholar
  34. Noda S, Aguirre SA, Bitmansour A, Brown JM, Sparer TE, Huang J, Mocarski ES (2006) Cytomegalovirus MCK-2 controls mobilization and recruitment of myeloid progenitor cells to facilitate dissemination. Blood 107:30–38.PubMedCrossRefGoogle Scholar
  35. Orloff SL (1999) Elimination of donor-specific alloreactivity by bone marrow chimerism prevents cytomegalovirus accelerated transplant vascular sclerosis in rat small bowel transplants. J Clin Virol 12:142.CrossRefGoogle Scholar
  36. Orloff SL, Yin Q, Corless CL, Orloff MS, Rabkin JM, Wagner CR (2000) Tolerance induced by bone marrow chimerism prevents transplant vascular sclerosis in a rat model of small bowel transplant chronic rejection. Transplantation 69:1295–1303.PubMedCrossRefGoogle Scholar
  37. Orloff SL, Streblow DN, Soderberg-Naucler C, Yin Q, Kreklywich C, Corless CL, Smith PA, Loomis CB, Mills LK, Cook JW, Bruggeman CA, Nelson JA, Wagner CR (2002) Elimination of donor-specific alloreactivity prevents cytomegalovirus-accelerated chronic rejection in rat small bowel and heart transplants. Transplantation 73:679–688.PubMedCrossRefGoogle Scholar
  38. Reinhardt B, Mertens T, Mayr-Beyrle U, Frank H, Luske A, Schierling K, Waltenberger J (2005a) HCMV infection of human vascular smooth muscle cells leads to enhanced expression of functionally intact PDGF beta-receptor. Cardiovasc Res 67:151–160.PubMedCrossRefGoogle Scholar
  39. Reinhardt B, Schaarschmidt P, Bossert A, Luske A, Finkenzeller G, Mertens T, Michel D (2005b) Upregulation of functionally active vascular endothelial growth factor by human cytomegalovirus. J Gen Virol 86:23–30.PubMedCrossRefGoogle Scholar
  40. Reinhardt B, Winkler R, Schaarschmidt P, Pretsch R, Zhou S, Vaida B, Schmid-Kotsas A, Michel D, Walther P, Bachem h, Mertens T (2006) Human cytomegalovirus-induced reduction of extracellular matrix proteins in vascular smooth muscle cell cultures: a pathomechanism in vasculopathies? J Gen Virol 87:2849–2858.PubMedCrossRefGoogle Scholar
  41. Rubin RH (1999) Importance of CMV in the transplant population. Transplant Infect Dis 1:3–7.CrossRefGoogle Scholar
  42. Schaarschmidt P, Reinhardt B, Michel D, Vaida B, Mayr K, Luske A, Baur R, Gschwend J, Kleinschmidt K, Kountidis S, Wenderoth U, Voisard R, Mertens T (1999) Altered expression of extracellular matrix in human-cytomegalovirus-infected cells and a human artery organ culture model to study its biological relevance. Intervirology 42:357–364.PubMedCrossRefGoogle Scholar
  43. Shahgasempour S, Woodroffe SB, Garnett HM (1997) Alterations in the expression of ELAM-1, ICAM-1 and VCAM-1 after in vitro infection of endothelial cells with a clinical isolate of human cytomegalovirus. Microbiol Immunol 41:121–129.PubMedGoogle Scholar
  44. Shibata S, Suzuki H, Nakatani M, Koba S, Geshi E, Katagiri T, Takeyama Y (2001) The involvement of vascular endothelial growth factor and flt-1 in the process of neointimal proliferation in pig coronary arteries following stent implantation. Histochem Cell Biol 116:471–481.PubMedCrossRefGoogle Scholar
  45. Soule JL, Streblow DN, Andoh TF, Kreklywich CN, Orloff SL (2006) Cytomegalovirus accelerates chronic allograft nephropathy in a rat renal transplant model with associated provocative chemokine profiles. Transplant Proc 38:3214–3220.PubMedCrossRefGoogle Scholar
  46. Sparer TE, Gosling J, Schall TJ, Mocarski ES (2004) Expression of human CXCR2 in murine neutrophils as a model for assessing cytomegalovirus chemokine vCXCL-1 function in vivo. J Interferon Cytokine Res 24:611–620.PubMedGoogle Scholar
  47. Speir E, Modali R, Huang ES, Leon MB, Shawl F, Finkel T, Epstein SE (1994) Potential role of human cytomegalovirus and p53 interaction in coronary restenosis. Science 265:391–394.PubMedCrossRefGoogle Scholar
  48. Streblow DN, Söderberg-Nauclér C, Vieira J, Smith P, Wakabayashi E, Rutchi F, Mattison K, Altschuler Y, Nelson JA (1999) The human cytomegalovirus chemokine receptor US28 mediates vascular smooth muscle cell migration. Cell 99:511–520.PubMedCrossRefGoogle Scholar
  49. Streblow DN, Kreklywich C, Yin Q, De La Melena VT, Corless CL, Smith PA, Brakebill C, Cook JW, Vink C, Bruggeman CA, Nelson JA, Orloff SL (2003) Cytomegalovirus-mediated upregulation of chemokine expression correlates with the acceleration of chronic rejection in rat heart transplants. J Virol 77:2182–2194.PubMedCrossRefGoogle Scholar
  50. Streblow DN, Kreklywich CN, Smith P, Soule JL, Meyer C, Yin S, Beisser P, Vink C, Nelson JA, Orloff SL (2005) Rat cytomegalovirus-accelerated transplant vascular sclerosis is reduced with mutation of the chemokine-receptor R33. Am J Transplant 5:436–442.PubMedCrossRefGoogle Scholar
  51. Streblow DN, van Cleef KW, Kreklywich CN, Meyer C, Smith P, Defilippis V, Grey F, Fruh K, Searles R, Bruggeman C, Vink C, Nelson JA, Orloff SL (2007) Rat cytomegalovirus gene expression in cardiac allograft recipients is tissue specific and does not parallel the profiles detected in vitro. J Virol 81:3816–3826.PubMedCrossRefGoogle Scholar
  52. Tikkanen JM, Kallio EA, Bruggeman CA, Koskinen PK, Lemstrom KB (2001a) Prevention of cytomegalovirus infection-enhanced experimental obliterative bronchiolitis by antiviral prophylaxis or immunosuppression in rat tracheal allografts. Am J Respir Crit Care Med 164:672–679.PubMedGoogle Scholar
  53. Tikkanen J, Kallio E, Pulkkinen V, Bruggeman C, Koskinen P, Lemstrom K (2001b) Cytomegalovirus infection-enhanced chronic rejection in the rat is prevented by antiviral prophylaxis. Transplant Proc 33:1801.PubMedCrossRefGoogle Scholar
  54. Tu W, Potena L, Stepick-Biek P, Liu L, Dionis KY, Luikart H, Fearon WF, Holmes TH, Chin C, Cooke JP, Valantine HA, Mocarski ES, Lewis DB (2006) T-cell immunity to subclinical cytomegalovirus infection reduces cardiac allograft disease. Circulation 114:1608–1615.PubMedCrossRefGoogle Scholar
  55. Valantine HA, Gao SZ, Santosh G et al (1999) Impact of prophylactic immediate post-transplant ganciclovir on development of transplant atherosclerosis. A post-hoc analysis of a randomized, placebo-controlled study. Circulation 100:61–66.PubMedGoogle Scholar
  56. Vieira J, Schall TJ, Corey L, Geballe AP (1998) Functional analysis of the human cytomegalovirus US28 gene by insertion mutagenesis with the green fluorescent protein gene. 72:8158–8165.Google Scholar
  57. Vliegen I, Duijvestijn A, Stassen F, Bruggeman C (2004) Murine cytomegalovirus infection directs macrophage differentiation into a pro-inflammatory immune phenotype: implications for atherogenesis. Microbes Infect 6:1056–1062.PubMedCrossRefGoogle Scholar
  58. Wegener J, Keese CR, Giaever I (2000) Electric cell-substrate impedance sensing (ECIS) as a noninvasive means to monitor the kinetics of cell spreading to artificial surfaces. Exp Cell Res 259:158–166.PubMedCrossRefGoogle Scholar
  59. Werner S, Grose R (2003) Regulation of wound healing by growth factors and cytokines. Physiol Rev 83:835–870.PubMedGoogle Scholar
  60. Wu TC, Hruban RH, Ambinder RF, Pizzorno W, Cameron DE, Baumgartner WA, Reitz BA, Hayward GS, Hutchins GM (1992) Demonstration of cytomegalovirus nucleic acids in the coronary arteries of transplanted hearts. Am J Pathol 140:739–747.PubMedGoogle Scholar
  61. Xiao C, Lachance B, Sunahara G, Luong JH (2002) An in-depth analysis of electric cell-substrate impedance sensing to study the attachment and spreading of mammalian cells. Anal Chem 74:1333–1339.PubMedCrossRefGoogle Scholar
  62. Zeng H, Waldman WJ, Yin DP, Knight DA, Shen J, Ma L, Meister GT, Chong AS, Williams JW (2005) Mechanistic study of malononitrileamide FK778 in cardiac transplantation and CMV infection in rats. Transplantation 79:17–22.PubMedCrossRefGoogle Scholar
  63. Zhou YF, Yu ZX, Wanishsawad C, Shou Z, Epstein SE (1999) The immediate early gene products of human cytomegalovirus increase vascular smooth muscle cell migration, proliferation, and expression of PDGF beta-receptor. Biochem Biophys Res Commun 256:608–613.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  • D. N. Streblow
    • 1
  • J. Dumortier
    • 1
  • A. V. Moses
    • 1
  • S. L. Orloff
    • 1
  • J. A. Nelson
    • 1
  1. 1.Vaccine and Gene Therapy InstituteOregon Health and Science UniversityPortlandUSA

Personalised recommendations