HCMV infection of human vascular smooth muscle cells leads to enhanced expression of functionally intact PDGF beta-receptor.
BACKGROUND
Cytomegaloviruses have been shown to promote atherogenesis in animal models. In humans, several epidemiological and clinical studies suggest involvement of the human cytomegalovirus (HCMV) in the development of atherosclerosis. HCMV is suspected to be associated with an enhanced restenosis rate and the occurrence of vasculopathies after solid organ transplantation. However, knowledge about the cellular and molecular bases of these findings is very limited.


RESULTS
Human coronary artery smooth muscle cells (HCASMC) were successfully infected with HCMV in vitro. Infection of HCASMC with all HCMV strains analyzed resulted in a substantial upregulation of the beta-receptor of platelet-derived growth factor (PDGFR-beta) expression as demonstrated by immunohistochemistry, immunofluorescence, FACS, and Western blot analysis. The amount of PDGFR-beta protein present in HCASMC rapidly increased after 12 h of infection and this difference persisted for 72 h post-infection. We showed by quantitative FACS analysis that the extent of PDGFR-beta upregulation differed significantly between the HCMV strains TB40E, Toledo, and AD169. The expression of insulin-like growth factor receptors as well as hepatocyte growth factor receptors, however, was down-modulated in HCMV-infected HCASMC. Most importantly, the HCMV-associated upregulation of PDGFR-beta protein resulted in functionally intact receptors. A significantly higher increase of proliferative activity following stimulation with PDGF-BB was observed in HCMV-infected HCASMC compared to the uninfected control.


CONCLUSIONS
Our data suggest that HCMV directly activates the PDGF system, which could promote atherogenesis and restenosis by activation of smooth muscle cell proliferation and neointima formation.
Reinhardt
Barbara
B
Department of Virology, Ulm University Medical Center, Ulm, Germany.
Mertens
Thomas
T
Mayr-Beyrle
Ulrike
U
Frank
Hedwig
H
Lüske
Anke
A
Schierling
Karina
K
Waltenberger
Johannes
J
D050197:Atherosclerosis / Q000378:metabolism / Q000821:virology*; D015153:Blotting, Western / Q000379:methods; D049109:Cell Proliferation; D002478:Cells, Cultured; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D005434:Flow Cytometry; D015967:Gene Expression Regulation, Viral; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D009131:Muscle, Smooth, Vascular / Q000821:virology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics*; D013045:Species Specificity; D018709:Statistics, Nonparametric
D020797:Receptor, Platelet-Derived Growth Factor beta