This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 104/11/1302    most recent CIRCRESAHA.109.197830v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Anisimov, A. Articles by Alitalo, K. PubMed PubMed Citation Articles by Anisimov, A. Articles by Alitalo, K. Related Collections Angiogenesis Cell biology/structural biology Growth factors/cytokines Gene therapy Endothelium/vascular type/nitric oxide

(Circulation Research. 2009;104:1302.)
© 2009 American Heart Association, Inc.

Integrative Physiology

Activated Forms of VEGF-C and VEGF-D Provide Improved Vascular Function in Skeletal Muscle

Andrey Anisimov, Annamari Alitalo, Petra Korpisalo, Jarkko Soronen, Seppo Kaijalainen, Veli-Matti Leppänen, Michael Jeltsch, Seppo Ylä-Herttuala, Kari Alitalo

From the Molecular/Cancer Biology Laboratory (A. Anisimov, J.S., S.K., V.-M.L., M.J., K.A.), Biomedicum Helsinki, Department of Pathology, Haartman Institute and Helsinki University Central Hospital, University of Helsinki, Finland; and Department of Biotechnology and Molecular Medicine (A. Alitalo, P.K., S.Y.-H.), A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, Finland.

Correspondence to Kari Alitalo, MD, PhD, Molecular/Cancer Biology Laboratory, Biomedicum Helsinki, PO Box 63, (Haartmaninkatu 8), University of Helsinki, FI-00014, Helsinki, Finland. E-mail Kari.Alitalo{at}helsinki.fi

The therapeutic potential of vascular endothelial growth factor (VEGF)-C and VEGF-D in skeletal muscle has been of considerable interest as these factors have both angiogenic and lymphangiogenic activities. Previous studies have mainly used adenoviral gene delivery for short-term expression of VEGF-C and VEGF-D in pig, rabbit, and mouse skeletal muscles. Here we have used the activated mature forms of VEGF-C and VEGF-D expressed via recombinant adeno-associated virus (rAAV), which provides stable, long-lasting transgene expression in various tissues including skeletal muscle. Mouse tibialis anterior muscle was transduced with rAAV encoding human or mouse VEGF-C or VEGF-D. Two weeks later, immunohistochemical analysis showed increased numbers of both blood and lymph vessels, and Doppler ultrasound analysis indicated increased blood vessel perfusion. The lymphatic vessels further increased at the 4-week time point were functional, as shown by FITC-lectin uptake and transport. Furthermore, receptor activation and arteriogenic activity were increased by an alanine substitution mutant of human VEGF-C (C137A) having an increased dimer stability and by a chimeric CAC growth factor that contained the VEGF receptor-binding domain flanked by VEGF-C propeptides, but only the latter promoted significantly more blood vessel perfusion when compared to the other growth factors studied. We conclude that long-term expression of VEGF-C and VEGF-D in skeletal muscle results in the generation of new functional blood and lymphatic vessels. The therapeutic value of intramuscular lymph vessels in draining tissue edema and lymphedema can now be evaluated using this model system.

Key Words: VEGF-C • VEGF-D • adeno-associated virus • angiogenesis • lymphangiogenesis • skeletal muscle