Adenoviral expression of vascular endothelial growth factor-C induces lymphangiogenesis in the skin.
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.
Enholm
B
B
Molecular/Cancer Biology Laboratory and Ludvig Institute for Cancer Research, Haartman Institute, University of Helsinki, Finland.
Karpanen
T
T
Jeltsch
M
M
Kubo
H
H
Stenback
F
F
Prevo
R
R
Jackson
D G
DG
Yla-Herttuala
S
S
Alitalo
K
K
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002455:Cell Division; D002460:Cell Line; D016228:Endothelial Growth Factors / Q000235:genetics / Q000502:physiology*; D004729:Endothelium, Lymphatic / Q000737:chemistry / Q000166:cytology / Q000502:physiology*; D004730:Endothelium, Vascular / Q000737:chemistry / Q000166:cytology; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D008222:Lymphokines / Q000235:genetics / Q000502:physiology; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D018919:Neovascularization, Physiologic / Q000502:physiology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000098:blood supply* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D040321:Vascular Endothelial Growth Factor Receptor-3; D042442:Vascular Endothelial Growth Factors; D033921:Vesicular Transport Proteins; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D016228:Endothelial Growth Factors; D006023:Glycoproteins; D008222:Lymphokines; D026901:Membrane Transport Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018809:Proliferating Cell Nuclear Antigen; D020794:Receptor Protein-Tyrosine Kinases; D017978:Receptors, Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D040321:Vascular Endothelial Growth Factor Receptor-3; D042442:Vascular Endothelial Growth Factors; D033921:Vesicular Transport Proteins; D001616:beta-Galactosidase; C119248:LYVE1 protein, human; C492273:LYVE1 protein, mouse