TRANSFORMATION OF RABBIT VASCULAR SMOOTH-MUSCLE CELLS BY HUMAN CYTOMEGALOVIRUS MORPHOLOGICAL TRANSFORMING REGION-1

The association of human cytomegalovirus with atherosclerosis and the monoclonal hypothesis of atherogenesis suggested that transformation o f vascular smooth muscle cells may be an outcome of the virus-host cel l interaction, To test this hypothesis, rabbit aorta smooth muscle cel ls were transfected with the morphological transforming region I (mtrI ) of human. cytomegalovirus (HCMV) linked to the neomycin resistance g ene. Foci of neomycin-resistant and morphologically transformed cells were isolated and expanded into fourteen RCMV strains, Eight of these strains acquired immortalization, but only one strain (RCMV-21) retain ed recombined viral sequences integrated in the cellular DNA. RCMV str ains were heterogeneous in their morphology, expression of smooth musc le cy-actin, growth, and mitogenic response to serum and fibroblast gr owth factor (FGF)-2 and -4. All RCMV strains assayed except RCMV-3 sho wed DNA synthesis in low serum medium and, with the exception of RCMV- 1 cells, all showed a significant mitogenic response to FGF-2 and FGF- 4. Maintenance of the transformed phenotype appeared independent of th e retention of the transforming viral sequences, which was suggestive of a ''hit-and-run'' mechanism. These results suggested that morpholog ical transformation by HCMV DNA sequences could enhance the mitogenic response of vascular smooth muscle cells to fibroblast growth factors.