Lymphangiogenic gene therapy with minimal blood vascular side effects

J Exp Med. 2002 Sep 16;196(6):719-30. doi: 10.1084/jem.20020587.


Recent work from many laboratories has demonstrated that the vascular endothelial growth factor-C/VEGF-D/VEGFR-3 signaling pathway is crucial for lymphangiogenesis, and that mutations of the Vegfr3 gene are associated with hereditary lymphedema. Furthermore, VEGF-C gene transfer to the skin of mice with lymphedema induced a regeneration of the cutaneous lymphatic vessel network. However, as is the case with VEGF, high levels of VEGF-C cause blood vessel growth and leakiness, resulting in tissue edema. To avoid these blood vascular side effects of VEGF-C, we constructed a viral vector for a VEGFR-3-specific mutant form of VEGF-C (VEGF-C156S) for lymphedema gene therapy. We demonstrate that VEGF-C156S potently induces lymphangiogenesis in transgenic mouse embryos, and when applied via viral gene transfer, in normal and lymphedema mice. Importantly, adenoviral VEGF-C156S lacked the blood vascular side effects of VEGF and VEGF-C adenoviruses. In particular, in the lymphedema mice functional cutaneous lymphatic vessels of normal caliber and morphology were detected after long-term expression of VEGF-C156S via an adeno associated virus. These results have important implications for the development of gene therapy for human lymphedema.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Dependovirus / genetics
  • Endothelial Growth Factors / genetics*
  • Genetic Therapy*
  • Lymphatic System / embryology
  • Lymphatic System / physiology*
  • Lymphedema / therapy
  • Mice
  • Neovascularization, Physiologic*
  • RNA, Messenger / analysis
  • Receptor Protein-Tyrosine Kinases / physiology*
  • Receptors, Growth Factor / physiology*
  • Vascular Endothelial Growth Factor C
  • Vascular Endothelial Growth Factor Receptor-3


  • Endothelial Growth Factors
  • RNA, Messenger
  • Receptors, Growth Factor
  • Vascular Endothelial Growth Factor C
  • Receptor Protein-Tyrosine Kinases
  • Vascular Endothelial Growth Factor Receptor-3