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Human Cytomegalovirus Downregulates Expression of Receptors for Platelet-Derived Growth Factor by Smooth Muscle Cells

Sara Gredmark ,^1,, Klas Strååt,^1, Mohammed Homman-Loudiyi,¹ Katja Kannisto,² and Cecilia Söderberg-Nauclér^1*

Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden,¹ Department of Medicine, Atherosclerosis Research Unit, King Gustaf V Research Institute, Karolinska Institutet, Stockholm, Sweden²

Received 6 October 2006/ Accepted 1 March 2007

Infection by human cytomegalovirus (HCMV) is associated with the development of vascular diseases and may cause severe brain damage in infected fetuses. Platelet-derived growth factor receptors alpha and beta (PDGFR- and -ß) control important cellular processes associated with atherosclerosis and fetal development. In the present investigation, our goal was to determine whether infection by HCMV can influence the expression of PDGFR- and -ß in human smooth muscle cells (SMCs). In connection with HCMV infection in vitro the levels of PDGFR- and -ß at the cell surface and in the total cellular protein of SMCs were reduced in parallel with decreases in the levels of the corresponding mRNAs. These effects were dependent on immediate-early (IE) or early (E) HCMV gene products, since inhibition of late genes did not prevent HCMV from affecting the expression of PDGFR- and -ß. The downregulation of PDGFR caused by HCMV was dose dependent. Furthermore, confocal microscopy revealed that the localization of PDGFR-ß was altered in HCMV-infected cells, in which this protein colocalized with proteins associated with endosomes (Rab4 and -5) and lysosomes (Lamp1 and -2), indicating entrance into pathways for protein degradation. Altogether these observations indicate that an IE and/or E HCMV protein(s) downregulates the expression of PDGFR- and -ß in SMCs. This phenomenon may disrupt cellular processes of importance in connection with cellular differentiation, migration, and/or proliferation. These observations may explain why congenital infection with HCMV can cause fetal brain damage.

Published ahead of print on 7 March 2007.

These authors contributed equally to this work and share first coauthorship.

Present address: Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142.