Human Cytomegalovirus Secretome Contains Factors That Induce Angiogenesis and Wound Healing

Veterans Affairs, Portland VAMC, Portland, OR; MMI, Department of Surgery, OHSU, Portland, OR; Vaccine and Gene Therapy Institute, OHSU, Portland, OR; Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA

^* To whom correspondence should be addressed. Email: nelsonj{at}ohsu.edu.

	Abstract

Human cytomegalovirus (HCMV) is implicated in the acceleration of a number of vascular diseases including transplant vascular sclerosis (TVS), the lesion associated with chronic rejection (CR) of solid organ transplants. Although the virus persists in the allograft throughout the course of disease, few cells are directly infected by CMV. This observation is in contrast to the global effects that CMV has on acceleration of TVS/CR suggesting that CMV infection indirectly promotes the vascular disease process. Recent transcriptome analysis of CMV-infected heart allografts indicates that the virus induces cytokines and growth factors associated with angiogenesis (AG) and wound healing (WH), suggesting that CMV may accelerate TVS/CR through the induction and secretion of AG/WH factors from infected cells. We analyzed virus-free supernatants from HCMV-infected cells (HCMV secretome) for growth factors by mass spectrometry and immunoassays and found the HCMV secretome contains over 1000 cellular proteins many of which are involved in AG/WH. Importantly, functional assays demonstrated that CMV but not herpes simplex virus secretomes not only induce AG/WH but also promote neo-vessel stabilization and endothelial cell survival for 2 weeks. These findings suggest that CMV acceleration of TVS occurs through virus induced growth factors and cytokines in the CMV secretome.