Adenoviral VEGF-C Overexpression Induces Blood Vessel Enlargement, Tortuosity, and Leakiness but No Sprouting Angiogenesis in the Skin or Mucous Membranes

FASEB J. 2002 Jul;16(9):1041-9. doi: 10.1096/fj.01-1042com.

Abstract

Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are important regulators of blood and lymphatic vessel growth and vascular permeability. The VEGF-C/VEGFR-3 signaling pathway is crucial for lymphangiogenesis, and heterozygous inactivating missense mutations of the VEGFR-3 gene are associated with hereditary lymphedema. However, VEGF-C can have potent effects on blood vessels because its receptor VEGFR-3 is expressed in certain blood vessels and because the fully processed form of VEGF-C also binds to the VEGFR-2 of blood vessels. To characterize the in vivo effects of VEGF-C on blood and lymphatic vessels, we have overexpressed VEGF-C via adenovirus- and adeno-associated virus-mediated transfection in the skin and respiratory tract of athymic nude mice. This resulted in dose-dependent enlargement and tortuosity of veins, which, along with the collecting lymphatic vessels were found to express VEGFR-2. Expression of angiopoietin 1 blocked the increased leakiness of the blood vessels induced by VEGF-C whereas vessel enlargement and lymphangiogenesis were not affected. However, angiogenic sprouting of new blood vessels was not observed in response to AdVEGF-C or AAV-VEGF-C. These results show that virally produced VEGF-C induces blood vessel changes, including vascular leak, but its angiogenic potency is much reduced compared with VEGF in normal skin.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics*
  • Angiopoietin-1
  • Animals
  • Blood Vessels / anatomy & histology
  • Blood Vessels / metabolism
  • Capillary Permeability / drug effects
  • Cell Line
  • Dependovirus / genetics
  • Endothelial Growth Factors / genetics*
  • Endothelial Growth Factors / metabolism
  • Genetic Vectors
  • Lymphatic System / growth & development
  • Lymphokines / genetics
  • Membrane Glycoproteins / pharmacology
  • Mice
  • Mice, Nude
  • Nasal Mucosa / blood supply
  • Neovascularization, Physiologic*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptors, Growth Factor / metabolism
  • Receptors, Vascular Endothelial Growth Factor
  • Skin / blood supply*
  • Skin / metabolism
  • Transfection
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor C
  • Vascular Endothelial Growth Factors

Substances

  • Angiopoietin-1
  • Angpt1 protein, mouse
  • Endothelial Growth Factors
  • Lymphokines
  • Membrane Glycoproteins
  • Receptors, Growth Factor
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor C
  • Vascular Endothelial Growth Factors
  • Receptor Protein-Tyrosine Kinases
  • Receptors, Vascular Endothelial Growth Factor