Adenoviral Expression of Vascular Endothelial Growth factor-C Induces Lymphangiogenesis in the Skin

Circ Res. 2001 Mar 30;88(6):623-9. doi: 10.1161/01.res.88.6.623.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Cell Division
  • Cell Line
  • Endothelial Growth Factors / genetics
  • Endothelial Growth Factors / physiology*
  • Endothelium, Lymphatic / chemistry
  • Endothelium, Lymphatic / cytology
  • Endothelium, Lymphatic / physiology*
  • Endothelium, Vascular / chemistry
  • Endothelium, Vascular / cytology
  • Gene Expression
  • Genetic Vectors / genetics
  • Glycoproteins / analysis
  • Humans
  • Immunohistochemistry
  • Lymphokines / genetics
  • Lymphokines / physiology
  • Membrane Transport Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Neovascularization, Physiologic / physiology*
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Proliferating Cell Nuclear Antigen / analysis
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptors, Growth Factor / metabolism
  • Receptors, Vascular Endothelial Growth Factor
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Skin / blood supply*
  • Skin / metabolism
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor C
  • Vascular Endothelial Growth Factor Receptor-3
  • Vascular Endothelial Growth Factors
  • Vesicular Transport Proteins
  • beta-Galactosidase / genetics
  • beta-Galactosidase / metabolism

Substances

  • Endothelial Growth Factors
  • Glycoproteins
  • LYVE1 protein, human
  • Lymphokines
  • Membrane Transport Proteins
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Proliferating Cell Nuclear Antigen
  • Receptors, Growth Factor
  • Recombinant Fusion Proteins
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor C
  • Vascular Endothelial Growth Factors
  • Vesicular Transport Proteins
  • Xlkd1 protein, mouse
  • Receptor Protein-Tyrosine Kinases
  • Receptors, Vascular Endothelial Growth Factor
  • Vascular Endothelial Growth Factor Receptor-3
  • beta-Galactosidase