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cells cultured in the presence of the HCMV secretome were able to repopulate the
wound with the same kinetics as with complete medium, although steady state
resistance levels were slightly lower. In contrast, cells cultured in SFM lacking
growth factors, the mock secretome, or the secretomes from HCMV UV- or
foscarnet-treated cells all were unable to repopulate the electrode, even over the
total 20 h measured. Similarly, cells incubated with a secretome derived from
HSV-1 infected cells also failed to mediate WH, suggesting that the WH effects
are specific for CMV. Importantly, these data clearly show that the HCMV secre-
tome contains factors that promote cell migration into a mechanical wound. The
ability of the HCMV secretome to mediate WH is due to active viral replication
since both UV-treated virions and foscarnet-treated cells did not promote WH.
Since foscarnet treatment of infected cells resulted in an inactive secretome, this
observation suggests that a late kinetic class of HCMV gene(s) is involved in the
generation of secretome WH factors. These observations correlate with studies in
human heart transplant patients as well as our own observations in heart trans-
plants in rats in which ganciclovir treatment prolongs graft survival.
Conclusions
There has been a steady progression to our understanding of role that HCMV
plays during the acceleration of vascular diseases such as atherosclerosis, resten-
osis, and transplant vasculopathy associated with the development of chronic
solid organ allograft rejection. This progress has been made through epidemio-
logic studies, the use of animal models of vascular disease and transplantation, as
well as through the use of
in vitro
models that mimic the clinical scenario. While
the precise mechanism(s) of action have yet to be fully elucidated, what has
become clear over the last couple of decades of study is that HCMV is capable of
modifying the extracellular host environment through the production and release
of biologically active cellular factors, including growth factors, cytokines, and
ECM-modifying enzymes. As we demonstrate here, the overall effect of this host
manipulation is that the HCMV secretome is capable of mediating angiogenesis
and wound healing, which are important processes that drive vascular disease
formation. Indeed, many of the factors that we identified in the HCMV secretome
were identified by microarray analysis in the rat allograft hearts, suggesting that
the factors involved in these two processes are similar. Future research meant to
identify the specific upstream gene targets that would make possible prevention
or abrogation of the HCMV-associated vasculopathy and chronic allograft rejec-
tion will broaden the therapeutic profile used to combat this very important
clinical problem.
Acknowledgements
S.L. Orloff was supported by a grant from the Department of Veterans
Affairs and from the National Institutes of Health (HL 66238-01); NIH grants were also awarded
to D.N. Streblow (HL083194) and J.A. Nelson (AI21640, HL65754, and HL71695). D.N.
Streblow is also supported by an AHA Scientist Development Grant.
