Lymphangiogenic gene therapy with minimal blood vascular side effects.
J Exp Med
; 196(6): 719-30, 2002 Sep 16.
Article
en En
| MEDLINE
| ID: mdl-12235206
ABSTRACT
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Terapia Genética
/
Factores de Crecimiento Endotelial
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Receptores de Factores de Crecimiento
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Proteínas Tirosina Quinasas Receptoras
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Neovascularización Fisiológica
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Sistema Linfático
Límite:
Animals
Idioma:
En
Revista:
J Exp Med
Año:
2002
Tipo del documento:
Article
País de afiliación:
Finlandia