, Volume 18, Issue 3, pp 313–326 | Cite as

VEGF-C and VEGF-C156S in the pro-lymphangiogenic growth factor therapy of lymphedema: a large animal study

  • Mikko T. VisuriEmail author
  • Krista M. Honkonen
  • Pauliina Hartiala
  • Tomi V. Tervala
  • Paavo J. Halonen
  • Heikki Junkkari
  • Nina Knuutinen
  • Seppo Ylä-Herttuala
  • Kari K. Alitalo
  • Anne M. Saarikko
Original Paper



VEGF-C156S, a lymphangiogenesis-specific form of vascular endothelial growth factor C (VEGF-C), has been considered as a promising candidate for the experimental pro-lymphangiogenic treatment, as it lacks potential angiogenic effects. As a precursor to future clinical trials, the therapeutic efficacy and blood vascular side effects of VEGF-C and VEGF-C156S were compared in a large animal model of secondary lymphedema. Combination of lymphatic growth factor treatment and autologous lymph node transfer was used to normalize the lymphatic anatomy after surgical excision of lymphatic tissue.


Lymph vessels around the inguinal lymph node of female domestic pigs were destroyed in order to impair the normal lymphatic drainage from the hind limb. Local injections of adenoviruses (Ad) encoding VEGF-C or VEGF-C156S were used to enhance the regrowth of the lymphatic vasculature. AdLacZ (β-galactosidase) and saline injections served as controls.


Both VEGF-C and VEGF-C156S induced growth of new lymphatic vessels in the area of excision, although lymphangiogenesis was notably stronger after VEGF-C treatment. Also the transferred lymph nodes were best-preserved in the VEGF-C-treated pigs. Despite the enlargement of blood vessels following the VEGF-C therapy, no signs of sprouting angiogenesis or increased blood vascular permeability in the form of increased wound exudate volumes were observed.


Our results show that VEGF-C provides the preferred alternative for growth factor therapy of lymphedema when compared to VEGF-C156S, due to the superior lymphangiogenic response and minor blood vessel effects. Furthermore, these observations suggest that activation of both VEGFR-2 and VEGFR-3 might be needed for efficient lymphangiogenesis.


Lymphedema Lymphangiogenesis Angiogenesis VEGF-C VEGF-C156S 



We wish to acknowledge Heikki Karhunen, Minna Törrönen, Heikki Pekonen and Seija Sahrio for their excellent technical assistance. This study was funded by the Academy of Finland, the Turku University Foundation and Special Governmental Funding (EVO) allocated to Turku University Central Hospital.

Conflict of interest

Drs. Saarikko and Alitalo have consultant agreements with Herantis Pharma Plc.

Ethical standard

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Supplementary material

10456_2015_9469_MOESM1_ESM.pdf (921 kb)
Supplementary material 1 (PDF 921 kb)


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Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  • Mikko T. Visuri
    • 1
    Email author
  • Krista M. Honkonen
    • 2
  • Pauliina Hartiala
    • 1
  • Tomi V. Tervala
    • 3
  • Paavo J. Halonen
    • 2
  • Heikki Junkkari
    • 2
  • Nina Knuutinen
    • 2
  • Seppo Ylä-Herttuala
    • 2
  • Kari K. Alitalo
    • 4
  • Anne M. Saarikko
    • 1
    • 5
  1. 1.Department of Plastic and General SurgeryTurku University HospitalTurkuFinland
  2. 2.A.I.Virtanen Institute for Molecular SciencesUniversity of Eastern FinlandKuopioFinland
  3. 3.Department of Plastic SurgeryKuopio University HospitalKuopioFinland
  4. 4.Wihuri Research Institute and Translational Cancer Biology ProgramUniversity of HelsinkiHelsinkiFinland
  5. 5.Cleft Unit, Department of Plastic SurgeryHelsinki University Central HospitalHelsinkiFinland

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