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Lymphangiogenic gene therapy with minimal blood vascular side effects.

Saaristo A, Veikkola T, Tammela T, Enholm B, Karkkainen MJ, Pajusola K, Bueler H, Ylä-Herttuala S, Alitalo K - J. Exp. Med. (2002)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki, Helsinki University Central Hospital, University of Helsinki, Finland.

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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Adenoviral VEGF-C156S has a minimal effect on vascular permeability. (A) The difference in permeability between the treated versus the control ear measured by Evans Blue concentration ratio (ng/mg). (B and C) Mouse thoracic cavities photographed after systemic administration of AdVEGF-C156S or AdVEGF-C (1 × 109 pfu). Note the accumulation of pleural fluid in the AdVEGF-C infected mouse (C) but not in the AdVEGF-C156S infected mouse (B).
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fig7: Adenoviral VEGF-C156S has a minimal effect on vascular permeability. (A) The difference in permeability between the treated versus the control ear measured by Evans Blue concentration ratio (ng/mg). (B and C) Mouse thoracic cavities photographed after systemic administration of AdVEGF-C156S or AdVEGF-C (1 × 109 pfu). Note the accumulation of pleural fluid in the AdVEGF-C infected mouse (C) but not in the AdVEGF-C156S infected mouse (B).

Mentions: To determine the effect of AdVEGF-C156S on blood vessel permeability, AdVEGF-C156S, AdVEGF-C, or AdLacZ viruses were injected into the right ears of nu/nu mice, while AdLacZ infected left ears served as controls. Extravasation of Evans Blue dye from ear blood vessels was measured 2 wk after infection. There was no statistically significant difference in the blood vessel permeability between the control ears and the AdVEGF-C156S–infected ears (Fig. 7 A), whereas the leakage of Evans Blue in the AdVEGF-C–treated ears was on an average 1.4 fold greater than in the AdLacZ-infected control ears (Fig. 7 A).


Lymphangiogenic gene therapy with minimal blood vascular side effects.

Saaristo A, Veikkola T, Tammela T, Enholm B, Karkkainen MJ, Pajusola K, Bueler H, Ylä-Herttuala S, Alitalo K - J. Exp. Med. (2002)

Adenoviral VEGF-C156S has a minimal effect on vascular permeability. (A) The difference in permeability between the treated versus the control ear measured by Evans Blue concentration ratio (ng/mg). (B and C) Mouse thoracic cavities photographed after systemic administration of AdVEGF-C156S or AdVEGF-C (1 × 109 pfu). Note the accumulation of pleural fluid in the AdVEGF-C infected mouse (C) but not in the AdVEGF-C156S infected mouse (B).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2194057&req=5

fig7: Adenoviral VEGF-C156S has a minimal effect on vascular permeability. (A) The difference in permeability between the treated versus the control ear measured by Evans Blue concentration ratio (ng/mg). (B and C) Mouse thoracic cavities photographed after systemic administration of AdVEGF-C156S or AdVEGF-C (1 × 109 pfu). Note the accumulation of pleural fluid in the AdVEGF-C infected mouse (C) but not in the AdVEGF-C156S infected mouse (B).
Mentions: To determine the effect of AdVEGF-C156S on blood vessel permeability, AdVEGF-C156S, AdVEGF-C, or AdLacZ viruses were injected into the right ears of nu/nu mice, while AdLacZ infected left ears served as controls. Extravasation of Evans Blue dye from ear blood vessels was measured 2 wk after infection. There was no statistically significant difference in the blood vessel permeability between the control ears and the AdVEGF-C156S–infected ears (Fig. 7 A), whereas the leakage of Evans Blue in the AdVEGF-C–treated ears was on an average 1.4 fold greater than in the AdLacZ-infected control ears (Fig. 7 A).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki, Helsinki University Central Hospital, University of Helsinki, Finland.

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.

Show MeSH
Related in: MedlinePlus