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

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-...

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Veröffentlicht in:Circulation research 2009-06, Vol.104 (11), p.1302-1312
Hauptverfasser: Anisimov, Andrey, Alitalo, Annamari, Korpisalo, Petra, Soronen, Jarkko, Kaijalainen, Seppo, Leppänen, Veli-Matti, Jeltsch, Michael, Ylä-Herttuala, Seppo, Alitalo, Kari
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container_end_page 1312
container_issue 11
container_start_page 1302
container_title Circulation research
container_volume 104
creator Anisimov, Andrey
Alitalo, Annamari
Korpisalo, Petra
Soronen, Jarkko
Kaijalainen, Seppo
Leppänen, Veli-Matti
Jeltsch, Michael
Ylä-Herttuala, Seppo
Alitalo, Kari
description 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.
doi_str_mv 10.1161/CIRCRESAHA.109.197830
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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. 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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.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Blood Vessels - physiology</subject><subject>Dimerization</subject><subject>Drug Stability</subject><subject>Fundamental and applied biological sciences. 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source MEDLINE; American Heart Association Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Journals@Ovid Complete
subjects Animals
Biological and medical sciences
Blood Vessels - physiology
Dimerization
Drug Stability
Fundamental and applied biological sciences. Psychology
Heart - physiology
Humans
Lymphatic Vessels - physiology
Mice
Mice, Transgenic
Muscle, Skeletal - blood supply
Muscle, Skeletal - physiology
Mutation
Polymorphism, Single Nucleotide
Recombinant Proteins - metabolism
Vascular Endothelial Growth Factor B - genetics
Vascular Endothelial Growth Factor B - physiology
Vascular Endothelial Growth Factor C - genetics
Vascular Endothelial Growth Factor C - physiology
Vascular Endothelial Growth Factor Receptor-2 - physiology
Vertebrates: cardiovascular system
title Activated Forms of VEGF-C and VEGF-D Provide Improved Vascular Function in Skeletal Muscle
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