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Human cytomegalovirus infection impairs endothelial cell chemotaxis by disturbing VEGF signaling and actin-polymerization

Barbara Reinhardt, Rinesh Godfrey, Guido Fellbrich, Hedwig Frank, Anke Lüske, Thomas Mertens, Johannes Waltenberger
DOI: http://dx.doi.org/10.1093/cvr/cvu204 cvu204 First published online: 16 September 2014

Abstract

Aims Human cytomegalovirus (HCMV) infection has been linked to the pathogenesis of vasculopathies; however, its pathogenic relevance remains to be established. A prerequisite for vascular repair is endothelial cell migration. We evaluated the influence of HCMV on chemokinesis and chemotactic response of human coronary artery endothelial cells (HCAEC) towards vascular endothelial growth factor (VEGF).

Methods and Results A virus dose dependent reduction in chemokinesis and VEGF-dependent chemotaxis was observed (p<0.05). UV-inactivated virus did not inhibit chemotaxis or chemokinesis indicating that viral gene expression is mandatory. We identified two HCMV-induced mechanisms explaining the reduction of chemotaxis: First, a nonambiguous reduction of VEGFR-2 protein was observed, due to decreased transcription. This protein down-modulation could not be inhibited by Ganciclovir. The remaining VEGFR-2 expressed on infected HCAEC were able to stimulate cell activation. Second, HCMV-infection influences actin-polymerization in HCAEC as shown by FACS analysis: Actin-polymerization was significantly reduced to 53% and 51% (p<0.05) compared to non-infected HCAEC at 24 h and 72 h p.i., respectively. Genetically and pharmacologically eliminated VEGFR-2 function resulted in a significant (p<0.05) reduction of VEGF-induced activation of actin- polymerization.

Conclusions We demonstrated a significant reduction of the chemotactic mobility of HCMV-infected HCAEC mediated by downmodulation of the VEGFR-2 and by inhibition of actin-polymerization. This VEGF resistance of HCMV-infected endothelial cells is likely to promote atherogenesis.

  • Human cytomegalovirus
  • endothelial cell
  • vascular endothelial growth factor
  • chemotaxis
  • signal transduction