© 2001 American Heart Association, Inc.
Molecular Medicine |
Adenoviral Expression of Vascular Endothelial Growth Factor-C Induces Lymphangiogenesis in the Skin
From the Molecular/Cancer Biology Laboratory and Ludvig Institute for Cancer Research (B.E., T.K., M.J., H.K., K.A.), Haartman Institute, University of Helsinki, Finland; Department of Pathology (F.S.), University of Oulu, Oulu, Finland; University of Oxford (R.P., D.G.J.), Molecular Immunology Group, Nuffield Department of Medicine, John Radcliffe Hospital, Headington, Oxford, UK; and A.I. Virtanen Institute and Department of Medicine (S.Y.-H.), University of Kuopio, Kuopio, Finland.
Correspondence to Kari Alitalo, MD, PhD, Molecular/Cancer Biology Laboratory, Biomedicum Helsinki, POB 63 (Haartmaninkatu 8), FIN-00014, Helsinki, Finland. E-mail Kari.Alitalo{at}Helsinki.fi
Abstract— The growth of blood and lymphatic vasculature is mediated in part by secreted polypeptides of the vascular endothelial growth factor (VEGF) family. The prototype VEGF binds VEGF receptor (VEGFR)-1 and VEGFR-2 and is angiogenic, whereas VEGF-C, which binds to VEGFR-2 and VEGFR-3, is either angiogenic or lymphangiogenic in different assays. We used an adenoviral gene transfer approach to compare the effects of these growth factors in adult mice. Recombinant adenoviruses encoding human VEGF-C or VEGF were injected subcutaneously into C57Bl6 mice or into the ears of nude mice. Immunohistochemical analysis showed that VEGF-C upregulated VEGFR-2 and VEGFR-3 expression and VEGF upregulated VEGFR-2 expression at 4 days after injection. After 2 weeks, histochemical and immunohistochemical analysis, including staining for the lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), the vascular endothelial marker platelet–endothelial cell adhesion molecule-1 (PECAM-1), and the proliferating cell nuclear antigen (PCNA) revealed that VEGF-C induced mainly lymphangiogenesis in contrast to VEGF, which induced only angiogenesis. These results have significant implications in the planning of gene therapy using these growth factors.
Key Words: angiogenesis • immunohistochemistry • viruses • vessels • revascularization
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|
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