Journal of Thrombosis and Thrombolysis

, Volume 33, Issue 2, pp 160–172 | Cite as

Human cytomegalovirus infection and atherothrombosis

  • Milan Popović
  • Katarina Smiljanić
  • Branislava Dobutović
  • Tatiana Syrovets
  • Thomas Simmet
  • Esma R. Isenović


Vascular endothelium, as a key regulator of hemostasis, mediates vascular dilatation, prevents platelet adhesion, and inhibits thrombin generation. Endothelial dysfunction caused by acute or chronic inflammation, such as in atherosclerosis, creates a proinflammatory environment which supports leukocyte transmigration toward inflammatory sites, and at the same time promotes coagulation, thrombin generation, and fibrin deposition in an attempt to close the wound. Life-long persistent infection with human cytomegalovirus (HCMV) has been associated with atherosclerosis. In vivo studies have revealed that HCMV infection of the vessel wall affects various cells including monocytes/macrophages, smooth muscle cells (SMCs) and endothelial cells (ECs). HCMV-infected SMCs within vascular lesions display enhanced proliferation and impaired apoptosis, which contribute to intima-media thickening, plaque formation and restenosis. Monocytes play a central role in the process of viral dissemination, whereas ECs may represent a viral reservoir, maintaining persistent infection in HCMV-infected atherosclerotic patients following the primary infection. Persistent infection leads to dysfunction of ECs and activates proinflammatory signaling involving nuclear factor κB, specificity protein 1, and phosphatidylinositol 3-kinase, as well as expression of platelet-derived growth factor receptor. Activation of these pathways promotes enhanced proliferation and migration of monocytes and SMCs into the intima of the vascular wall as well as lipid accumulation and expansion of the atherosclerotic lesion. Moreover, HCMV infection induces enhanced expression of endothelial adhesion molecules and modifies the proteolytic balance in monocytes and macrophages. As a consequence, infected endothelium recruits naive monocytes from the blood stream, and the concomitant interaction between infected ECs and monocytes enables virus transfer to migrating monocytes. Endothelial damage promotes thrombin generation linking inflammation and coagulation. HCMV, in turn, enhances the thrombin generation. The virus carries on its surface the molecular machinery necessary to initiate thrombin generation, and in addition, may interact with the prothrombinase protein complex thereby facilitating thrombin generation. Thus, infection of endothelium may significantly increase the production of thrombin. This might not only contribute to thrombosis in patients with atherosclerosis, but might also induce thrombin-dependent proinflammatory cell activation. This review summarizes the existing evidence on the role of HCMV in vascular inflammation.


HCMV Coagulation Vascular inflammation Atherosclerosis 





Serine/threonine protein kinase




Endothelial cells


Human cytomegalovirus


Epidermal growth factor receptor


Herpes simplex virus 1 (human herpes virus 1)


Herpes simplex virus 2 (human herpes virus 2)




Intercellular adhesion molecule-1


Mitogen activated protein kinase


Macrophage colony-stimulating factor


Nuclear factor-κB


Phosphatidylinositol 3-kinase


Platelet-derived growth factor receptor


Platelet-derived growth factor receptor-β


Procoagulant phospholipid


Specificity protein 1


Smooth muscle cells


Vascular cell adhesion molecule-1


Vascular smooth muscle cells


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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Milan Popović
    • 1
  • Katarina Smiljanić
    • 1
  • Branislava Dobutović
    • 1
  • Tatiana Syrovets
    • 2
  • Thomas Simmet
    • 2
  • Esma R. Isenović
    • 1
  1. 1.Department for Radiobiology and Molecular Genetics, Vinča InstituteUniversity of BelgradeBelgradeSerbia
  2. 2.Institute of Pharmacology of Natural Products & Clinical PharmacologyUlm UniversityUlmGermany

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