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Activated forms of VEGF-C and VEGF-D provide improved vascular function in skeletal muscle

Identifieur interne : 006415 ( Main/Exploration ); précédent : 006414; suivant : 006416

Activated forms of VEGF-C and VEGF-D provide improved vascular function in skeletal muscle

Auteurs : Andrey Anisimov [Finlande] ; Annamari Alitalo [Finlande] ; Petra Korpisalo [Finlande] ; Jarkko Soronen [Finlande] ; Seppo Kaijalainen [Finlande] ; Veli-Matti Lepp Nen [Finlande] ; Michael Jeltsch [Finlande] ; Seppo Yl Herttuala [Finlande] ; Kari Alitalo [Finlande]

Source :

RBID : PMC:2776655

Descripteurs français

English descriptors

Abstract

The therapeutic potential of vascular endothelial growth factor C (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 employed 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 four-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.


Url:
DOI: 10.1161/CIRCRESAHA.109.197830
PubMed: 19443835
PubMed Central: 2776655


Affiliations:


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Le document en format XML

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<keywords scheme="MESH" xml:lang="fr">
<term>Animaux</term>
<term>Dimérisation</term>
<term>Humains</term>
<term>Muscles squelettiques</term>
<term>Mutation</term>
<term>Polymorphisme de nucléotide simple</term>
<term>Souris</term>
<term>Souris transgéniques</term>
<term>Stabilité de médicament</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front>
<div type="abstract" xml:lang="en">
<p id="P1">The therapeutic potential of vascular endothelial growth factor C (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 employed 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 four-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.</p>
</div>
</front>
</TEI>
<affiliations>
<list>
<country>
<li>Finlande</li>
</country>
<region>
<li>Uusimaa</li>
</region>
<settlement>
<li>Helsinki</li>
</settlement>
<orgName>
<li>Université d'Helsinki</li>
</orgName>
</list>
<tree>
<country name="Finlande">
<region name="Uusimaa">
<name sortKey="Anisimov, Andrey" sort="Anisimov, Andrey" uniqKey="Anisimov A" first="Andrey" last="Anisimov">Andrey Anisimov</name>
</region>
<name sortKey="Alitalo, Annamari" sort="Alitalo, Annamari" uniqKey="Alitalo A" first="Annamari" last="Alitalo">Annamari Alitalo</name>
<name sortKey="Alitalo, Kari" sort="Alitalo, Kari" uniqKey="Alitalo K" first="Kari" last="Alitalo">Kari Alitalo</name>
<name sortKey="Jeltsch, Michael" sort="Jeltsch, Michael" uniqKey="Jeltsch M" first="Michael" last="Jeltsch">Michael Jeltsch</name>
<name sortKey="Kaijalainen, Seppo" sort="Kaijalainen, Seppo" uniqKey="Kaijalainen S" first="Seppo" last="Kaijalainen">Seppo Kaijalainen</name>
<name sortKey="Korpisalo, Petra" sort="Korpisalo, Petra" uniqKey="Korpisalo P" first="Petra" last="Korpisalo">Petra Korpisalo</name>
<name sortKey="Lepp Nen, Veli Matti" sort="Lepp Nen, Veli Matti" uniqKey="Lepp Nen V" first="Veli-Matti" last="Lepp Nen">Veli-Matti Lepp Nen</name>
<name sortKey="Soronen, Jarkko" sort="Soronen, Jarkko" uniqKey="Soronen J" first="Jarkko" last="Soronen">Jarkko Soronen</name>
<name sortKey="Yl Herttuala, Seppo" sort="Yl Herttuala, Seppo" uniqKey="Yl Herttuala S" first="Seppo" last="Yl Herttuala">Seppo Yl Herttuala</name>
</country>
</tree>
</affiliations>
</record>

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