¹Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA

Correspondence: Daniel R. Salomon, Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. E-mail: dsalomon@scripps.edu

Received 3 May 2006; Accepted 26 March 2007; Published online 1 May 2007.

Abstract

Therapies that stimulate angiogenesis show promise in revascularization of transplanted or ischemic tissues. Viral macrophage inflammatory protein-II (vMIP-II) is encoded by human herpesvirus 8, and it can be both immunosuppressive and proangiogenic. However, little has been done to characterize the potential of vMIP-II-induced angiogenesis. We engineered a vMIP-II lentiviral gene vector, transduced both mature endothelial cells and progenitors, and transplanted these in Matrigel templates as an in vivo angiogenesis model. Our results show that vMIP-II promotes new, functional, branching, and segmented vessels associated with smooth muscle cells and connected with the host vasculature. Angiogenesis is enhanced through host cells as well as through transplanted vMIP-expressing endothelial cells. As a proof-of-concept for using vMIP-II in clinical applications, we showed that islets co-transplanted with endothelial cells expressing vMIP-II were revascularized and survived in Matrigel templates, whereas no islets survived under control conditions. vMIP-II up-regulates the expression of multiple proangiogenic factors that can have a synergistic effect. These include vascular endothelial growth factor (VEGF), kinase insert domain receptor, neuropilin 2, carcinoembryonic antigen-related cell adhesion molecule 1, interleukin-1, fibronectin, and integrins 3, 4, and 5. These results provide the first demonstration that vMIP-II is proangiogenic in vivo and can deliver this function to endothelial progenitors as well as to mature endothelial cells through vector-mediated gene delivery.