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

[lymphedemapeople]

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

Circ Res. 2009 May

Anisimov A, Alitalo A, Korpisalo P, Soronen J, Kaijalainen S, Leppänen
VM, Jeltsch M, Ylä-Herttuala S, Alitalo K.
Molecular/Cancer Biology Laboratory, Biomedicum Helsinki, Department
of Pathology, Haartman Institute and Helsinki University Central
Hospital, University of Helsinki, Finland; and Department of
Biotechnology and Molecular Medicine, A. I. Virtanen Institute for
Molecular Sciences, University of Kuopio, Finland.

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.

http://circres.ahajournals.org/cgi/content/abstract/CIRCRESAHA.109.197830v1