title: Distinct architecture of lymphatic vessels induced by chimeric vascular endothelial growth factor-C/vascular endothelial growth factor heparin-binding domain fusion proteins.
abstract: Vascular endothelial growth factor (VEGF)-C and VEGF-D are composed of the receptor-binding VEGF homology domain and a carboxy-terminal silk homology domain that requires proteolytic cleavage for growth factor activation. Here, we explored whether the C-terminal heparin-binding domain of the VEGF(165) or VEGF(189) isoform also containing neuropilin-binding sequences could substitute for the silk homology domain of VEGF-C. Such VEGF-C/VEGF-heparin-binding domain chimeras were produced and shown to activate VEGF-C receptors, and, when expressed in tissues via adenovirus or adeno-associated virus vectors, stimulated lymphangiogenesis in vivo. However, both chimeras induced a distinctly different pattern of lymphatic vessels when compared with VEGF-C. Whereas VEGF-C-induced vessels were initially a dense network of small diameter vessels, the lymphatic vessels induced by the chimeric growth factors tended to form directly along tissue borders, along basement membranes that are rich in heparan sulfate. For example, in skeletal muscle, the chimeras induced formation of lumenized lymphatic vessels more efficiently than wild-type VEGF-C. We conclude that the matrix-binding domain of VEGF can target VEGF-C activity to heparin-rich basement membrane structures. These properties may prove useful for tissue engineering and attempts to regenerate lymphatic vessels in lymphedema patients.
authors.affiliation: Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki, the Haartman Institute and Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: Tuomas
authors.initials: T
authors.lastname: Tammela
authors.forename: Yulong
authors.initials: Y
authors.lastname: He
authors.forename: Johannes
authors.initials: J
authors.lastname: Lyytikkä
authors.forename: Michael
authors.initials: M
authors.lastname: Jeltsch
authors.forename: Johanna
authors.initials: J
authors.lastname: Markkanen
authors.forename: Katri
authors.initials: K
authors.lastname: Pajusola
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D006493:Heparin / Q000378:metabolism*; D006801:Humans; D042583:Lymphangiogenesis / Q000187:drug effects; D042601:Lymphatic Vessels / Q000187:drug effects*; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000494:pharmacology*; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism
chemical_list: D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D006493:Heparin; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3