Lymphangiogenic Gene Therapy With Minimal Blood Vascular Side Effects

2002/09/16 by Anne Saaristo, Tanja Veikkola, Tuomas Tammela +8 · 169 citations
Biochemistry, Genetics and Molecular Biology · Medicine · #Angiogenesis and VEGF in Cancer #Biology #Blood vessel #Cancer #Cancer research #Gene #Genetic enhancement #Genetics #Immunology #Internal medicine #Lymphangiogenesis #Lymphatic System and Diseases #Lymphatic system #Lymphatic vessel #Lymphedema #Medicine #Metastasis #Pathology #Sympathectomy and Hyperhidrosis Treatments #VEGF receptors #Vascular endothelial growth factor #Vascular endothelial growth factor A #Vascular endothelial growth factor C

paper · pdf · doi:10.1084/jem.20020587

published in The Journal of Experimental Medicine 196(6), 719-730 (Rockefeller University Press)

openalex publication_date 2002/09/16 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/31

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.

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