Cytomegalovirus aggravates intimal hyperplasia in rats by stimulating smooth muscle cell proliferation.
Epidemiological and animal studies suggest a role for cytomegalovirus (CMV) in restenosis. Previously, we demonstrated that proliferating smooth muscle cells (SMCs) in the injured arterial wall are particularly susceptible to CMV-induced effects. Therefore, we hypothesised that, depending on the time point of infection after vascular injury, CMV infection may affect cell proliferation either in the media or in the neointima, thereby aggravating the process of restenosis. In the present study, we focused on the individual layers of the arterial wall by evaluating, besides the neointima-to-media ratio, the medial and neointimal area and cellularity in the rat femoral artery. Vascular injury was photochemically induced in rat femoral arteries. Immediately or 14 days thereafter, rats were infected with rat CMV (RCMV) or mock infected. The presence of RCMV in the vascular wall was determined at 3, 5, 14 and 35 days after infection by quantitative real-time PCR. When rats were infected immediately after injury, a significant increase was seen only in the medial but not in the neointimal cross-sectional area. On the other hand, when rats were infected 14 days after the initial injury, a significant increase was only seen in the neointimal area, thereby confirming our hypothesis that RCMV infection primary affects proliferating SMCs. As the mean number of SMCs per microm2 in both cell layers was unchanged despite an increase in cross-sectional area, this implies that RCMV stimulated SMC proliferation. Furthermore, these vascular effects were observed without the virus being abundantly present in the vascular wall, suggesting that inflammatory and immune-mediated responses to RCMV infection are more important in aggravating the response to vascular injury than the virus itself.
Kloppenburg
Geoffrey
G
Department of Medical Microbiology and Maastricht Infection Centre, University Hospital Maastricht, P. Debyelaan 25, P.O. Box 5800, 6202 AZ Maastricht, the Netherlands.
de Graaf
Rick
R
Herngreen
Selma
S
Grauls
Gert
G
Bruggeman
Cathrien
C
Stassen
Frank
F
D000818:Animals; D001161:Arteriosclerosis / Q000097:blood / Q000473:pathology / Q000821:virology*; D049109:Cell Proliferation; D003587:Cytomegalovirus / Q000235:genetics / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000150:complications / Q000473:pathology*; D006965:Hyperplasia / Q000209:etiology; D009131:Muscle, Smooth, Vascular / Q000473:pathology / Q000821:virology*; D051381:Rats; D017539:Tunica Intima / Q000293:injuries / Q000473:pathology / Q000821:virology*