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 |
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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. The therapeutic value of intramuscular lymph vessels in draining tissue edema and lymphedema can now be evaluated using this model system.</description><identifier>ISSN: 0009-7330</identifier><identifier>EISSN: 1524-4571</identifier><identifier>DOI: 10.1161/CIRCRESAHA.109.197830</identifier><identifier>PMID: 19443835</identifier><identifier>CODEN: CIRUAL</identifier><language>eng</language><publisher>Hagerstown, MD: American Heart Association, Inc</publisher><subject>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</subject><ispartof>Circulation research, 2009-06, Vol.104 (11), p.1302-1312</ispartof><rights>2009 American Heart Association, Inc.</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5890-12a3adc77fe8b954632172c06499444127109a05b3760060f3f9bb56e53e8b803</citedby><cites>FETCH-LOGICAL-c5890-12a3adc77fe8b954632172c06499444127109a05b3760060f3f9bb56e53e8b803</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3674,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21615559$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19443835$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Anisimov, Andrey</creatorcontrib><creatorcontrib>Alitalo, Annamari</creatorcontrib><creatorcontrib>Korpisalo, Petra</creatorcontrib><creatorcontrib>Soronen, Jarkko</creatorcontrib><creatorcontrib>Kaijalainen, Seppo</creatorcontrib><creatorcontrib>Leppänen, Veli-Matti</creatorcontrib><creatorcontrib>Jeltsch, Michael</creatorcontrib><creatorcontrib>Ylä-Herttuala, Seppo</creatorcontrib><creatorcontrib>Alitalo, Kari</creatorcontrib><title>Activated Forms of VEGF-C and VEGF-D Provide Improved Vascular Function in Skeletal Muscle</title><title>Circulation research</title><addtitle>Circ Res</addtitle><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.</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. Psychology</subject><subject>Heart - physiology</subject><subject>Humans</subject><subject>Lymphatic Vessels - physiology</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Muscle, Skeletal - blood supply</subject><subject>Muscle, Skeletal - physiology</subject><subject>Mutation</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Recombinant Proteins - metabolism</subject><subject>Vascular Endothelial Growth Factor B - genetics</subject><subject>Vascular Endothelial Growth Factor B - physiology</subject><subject>Vascular Endothelial Growth Factor C - genetics</subject><subject>Vascular Endothelial Growth Factor C - physiology</subject><subject>Vascular Endothelial Growth Factor Receptor-2 - physiology</subject><subject>Vertebrates: cardiovascular system</subject><issn>0009-7330</issn><issn>1524-4571</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkU9v1DAQxS0EokvhI4B8gVuW8f_4grQKu-1KRaAWeuBiOYnDhnrjxU624ttjlFULJ4_Gv_c8nofQawJLQiR5X22vq-v1zepytSSgl0SrksETtCCC8oILRZ6iBQDoQjEGZ-hFSj8BCGdUP0dnRHPOSiYW6PuqGfujHV2LNyHuEw4dvl1fbIoK26Gdy4_4SwzHvnV4uz_kKrO3NjWTtxFvpiEbhAH3A765c96N1uNPU2q8e4meddYn9-p0nqNvm_XX6rK4-nyxrVZXRSNKDQWhltm2UapzZa0Fl4wSRRuQXOcpOaEq_8-CqJmSABI61um6FtIJlgUlsHP0YfY9TPXetY0bxmi9OcR-b-NvE2xv_r8Z-p35EY6GKiWlENng3ckghl-TS6PZ96lx3tvBhSkZqRgFqXgGxQw2MaQUXffwCAHzNxXzmEpuaTOnknVv_p3wUXWKIQNvT0Deq_VdtEPTpweOZmshhM4cn7n74EcX052f7l00O2f9uDM5bmBAaEFz7nlTAorcIcD-AEvBo_o</recordid><startdate>20090605</startdate><enddate>20090605</enddate><creator>Anisimov, Andrey</creator><creator>Alitalo, Annamari</creator><creator>Korpisalo, Petra</creator><creator>Soronen, Jarkko</creator><creator>Kaijalainen, Seppo</creator><creator>Leppänen, Veli-Matti</creator><creator>Jeltsch, Michael</creator><creator>Ylä-Herttuala, Seppo</creator><creator>Alitalo, Kari</creator><general>American Heart Association, Inc</general><general>Lippincott Williams & Wilkins</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20090605</creationdate><title>Activated Forms of VEGF-C and VEGF-D Provide Improved Vascular Function in Skeletal Muscle</title><author>Anisimov, Andrey ; Alitalo, Annamari ; Korpisalo, Petra ; Soronen, Jarkko ; Kaijalainen, Seppo ; Leppänen, Veli-Matti ; Jeltsch, Michael ; Ylä-Herttuala, Seppo ; Alitalo, Kari</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5890-12a3adc77fe8b954632172c06499444127109a05b3760060f3f9bb56e53e8b803</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Blood Vessels - physiology</topic><topic>Dimerization</topic><topic>Drug Stability</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Heart - physiology</topic><topic>Humans</topic><topic>Lymphatic Vessels - physiology</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Muscle, Skeletal - blood supply</topic><topic>Muscle, Skeletal - physiology</topic><topic>Mutation</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Recombinant Proteins - metabolism</topic><topic>Vascular Endothelial Growth Factor B - genetics</topic><topic>Vascular Endothelial Growth Factor B - physiology</topic><topic>Vascular Endothelial Growth Factor C - genetics</topic><topic>Vascular Endothelial Growth Factor C - physiology</topic><topic>Vascular Endothelial Growth Factor Receptor-2 - physiology</topic><topic>Vertebrates: cardiovascular system</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Anisimov, Andrey</creatorcontrib><creatorcontrib>Alitalo, Annamari</creatorcontrib><creatorcontrib>Korpisalo, Petra</creatorcontrib><creatorcontrib>Soronen, Jarkko</creatorcontrib><creatorcontrib>Kaijalainen, Seppo</creatorcontrib><creatorcontrib>Leppänen, Veli-Matti</creatorcontrib><creatorcontrib>Jeltsch, Michael</creatorcontrib><creatorcontrib>Ylä-Herttuala, Seppo</creatorcontrib><creatorcontrib>Alitalo, Kari</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Circulation research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Anisimov, Andrey</au><au>Alitalo, Annamari</au><au>Korpisalo, Petra</au><au>Soronen, Jarkko</au><au>Kaijalainen, Seppo</au><au>Leppänen, Veli-Matti</au><au>Jeltsch, Michael</au><au>Ylä-Herttuala, Seppo</au><au>Alitalo, Kari</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Activated Forms of VEGF-C and VEGF-D Provide Improved Vascular Function in Skeletal Muscle</atitle><jtitle>Circulation research</jtitle><addtitle>Circ Res</addtitle><date>2009-06-05</date><risdate>2009</risdate><volume>104</volume><issue>11</issue><spage>1302</spage><epage>1312</epage><pages>1302-1312</pages><issn>0009-7330</issn><eissn>1524-4571</eissn><coden>CIRUAL</coden><abstract>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.</abstract><cop>Hagerstown, MD</cop><pub>American Heart Association, Inc</pub><pmid>19443835</pmid><doi>10.1161/CIRCRESAHA.109.197830</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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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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