Mechanisms of Cytomegalovirus-Accelerated Vascular Disease: Induction of Paracrine Factors That Promote Angiogenesis and
Human cytomegalovirus (HCMV) is associated with the acceleration of a number of vascular diseases such as atherosclerosis, restenosis, and transplant vascular sclerosis (TVS). All of these diseases are the result of either mechanical or immunemediated inj
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Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tissue Repair and Angiogenic Factors Mediate TVS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Animal Models of CMV-Accelerated Graft Rejection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RCMV Accelerates TVS and CR in a Rat Heart Transplantation Model . . . . . . . . . . . . . . . RCMV Induces Allograft AG and WH Genes During the Acceleration of TVS . . . . . . . . . In Vitro Models of HCMV-Mediated Wound Healing and Angiogenesis . . . . . . . . . . . . . . . What Factors Constitute the HCMV Secretome? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HCMV Secretome Induces Angiogenesis in Endothelial Cells. . . . . . . . . . . . . . . . . . . . . . . HCMV Secretome Induces Wound Healing in Endothelial Cells . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract Human cytomegalovirus (HCMV) is associated with the acceleration of a number of vascular diseases such as atherosclerosis, restenosis, and transplant vascular sclerosis (TVS). All of these diseases are the result of either mechanical or immunemediated injury followed by inflammation and subsequent smooth muscle cell (SMC) migration from the vessel media to the intima and proliferation that culminates in vessel narrowing. A number of epidemiological and animal studies have demonstrated that CMV significantly accelerates TVS and chronic rejection (CR) in solid organ allografts. In addition, treatment of human recipients and animals alike with the antiviral drug ganciclovir results in prolonged survival of the allograft, indicating that CMV replication is a requirement for acceleration of disease. However, although virus persists in the allograft throughout the course of disease, the number of directly infected cells does not account for the global effects that the virus has on the acceleration of TVS and CR. Recent investigations of up- and downregulated cellular genes in infected allografts in comparison to native heart has demonstrated that rat CMV (RCMV) upregulates genes involved in wound healing (WH) and angiogenesis (AG). Consistent with this result, D.N. Streblow Vaccine and Gene Therapy Institute and Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97201, USA [email protected]
T.E. Shenk and M.F. Stinski (eds.), Human Cytomegalovirus. Current Topics in Microbiology and Immunology 325. © Springer-Verlag Berlin Heidelberg 2008
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we have found that supernatants from HCMV-infected cells (HCMV secretome) induce WH and AG using in vitro models. Taken together, these
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