Lentiviral gene delivery of vMIP-II to transplanted endothelial cells and endothelial progenitors is proangiogenic in vivo.
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-1alpha, fibronectin, and integrins alpha3, alpha4, and alpha5. 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.
Cherqui
Stephanie
S
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA.
Kingdon
Kenneth M
KM
Thorpe
Camille
C
Kurian
Sunil M
SM
Salomon
Daniel R
DR
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007515:Islets of Langerhans / Q000098:blood supply / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D007797:Laminin / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics*; D051379:Mice; D018919:Neovascularization, Physiologic; D011509:Proteoglycans / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics*
D018925:Chemokines; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; C108059:vMIP-II; C059485:matrigel; D003094:Collagen