Lymphangiogenic gene therapy with minimal blood vascular side effects.
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.
Saaristo
Anne
A
Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki, Helsinki University Central Hospital, University of Helsinki, Finland.
Veikkola
Tanja
T
Tammela
Tuomas
T
Enholm
Berndt
B
Karkkainen
Marika J
MJ
Pajusola
Katri
K
Bueler
Hansruedi
H
Ylä-Herttuala
Seppo
S
Alitalo
Kari
K
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000229:Dependovirus / Q000235:genetics; D016228:Endothelial Growth Factors / Q000235:genetics*; D015316:Genetic Therapy; D008208:Lymphatic System / Q000196:embryology / Q000502:physiology*; D008209:Lymphedema / Q000628:therapy; D051379:Mice; D018919:Neovascularization, Physiologic; D012333:RNA, Messenger / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000502:physiology*; D042582:Vascular Endothelial Growth Factor C; D040321:Vascular Endothelial Growth Factor Receptor-3
D016228:Endothelial Growth Factors; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D042582:Vascular Endothelial Growth Factor C; D020794:Receptor Protein-Tyrosine Kinases; D040321:Vascular Endothelial Growth Factor Receptor-3