Gene transfer using the mature form of VEGF-D reduces neointimal thickening through nitric oxide-dependent mechanism

Gene transfer to the vessel wall using vascular endothelial growth factors (VEGFs) has shown therapeutic potential for the treatment of restenosis. In this study, we evaluated the effect of catheter-mediated adenoviral (Ad) gene transfer of the mature form of VEGF-D (VEGF-D ΔNΔC ) in balloon-denuded...

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Veröffentlicht in:Gene therapy 2005-06, Vol.12 (12), p.980-987
Hauptverfasser: Rutanen, J, Turunen, A-M, Teittinen, M, Rissanen, T T, Heikura, T, Koponen, J K, Gruchala, M, Inkala, M, Jauhiainen, S, Hiltunen, M O, Turunen, M P, Stacker, S A, Achen, M G, Ylä-Herttuala, S
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container_issue 12
container_start_page 980
container_title Gene therapy
container_volume 12
creator Rutanen, J
Turunen, A-M
Teittinen, M
Rissanen, T T
Heikura, T
Koponen, J K
Gruchala, M
Inkala, M
Jauhiainen, S
Hiltunen, M O
Turunen, M P
Stacker, S A
Achen, M G
Ylä-Herttuala, S
description Gene transfer to the vessel wall using vascular endothelial growth factors (VEGFs) has shown therapeutic potential for the treatment of restenosis. In this study, we evaluated the effect of catheter-mediated adenoviral (Ad) gene transfer of the mature form of VEGF-D (VEGF-D ΔNΔC ) in balloon-denuded cholesterol-fed rabbit aorta. AdLacZ was used as a control. Transduced VEGF-D ΔNΔC mRNA was detectable in the arterial wall with RT-PCR at 6, 14 and 28 days. Gene transfer efficiency as detected with X-gal staining 6 days after the AdLacZ transduction was 1.91±1.32% in intima. AdVEGF-D ΔNΔC gene transfer led to 52% reduction in intima/media ratio (I/M) as compared to the AdLacZ controls at 14 days time point. At 6 days there were no differences in I/M, but the number of macrophages in the vessel wall was 85% lower in the AdVEGF-D ΔNΔC group as compared to the controls. The therapeutic effect was no longer detectable 28 days after the gene transfer. The therapeutic effect of VEGF-D ΔNΔC was nitric oxide (NO)-dependent as the feeding of NO synthase inhibitor, L -NAME, blocked the reduction in intimal thickening. It is concluded that AdVEGF-D ΔNΔC gene transfer reduces intimal thickening and macrophage influx into the vessel wall in balloon-denuded rabbit aortas.
doi_str_mv 10.1038/sj.gt.3302489
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Cell and gene therapy ; Tunica Intima - metabolism ; Tunica Intima - pathology ; Vascular endothelial growth factor ; Vascular Endothelial Growth Factor D - genetics ; Vascular Endothelial Growth Factor D - metabolism</subject><ispartof>Gene therapy, 2005-06, Vol.12 (12), p.980-987</ispartof><rights>Springer Nature Limited 2005</rights><rights>2005 INIST-CNRS</rights><rights>COPYRIGHT 2005 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jun 2005</rights><rights>Nature Publishing Group 2005.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c617t-e1519defee2c7b396e2bfe58489607f1174be6577e443459e9ee1e9db6c83d0f3</citedby><cites>FETCH-LOGICAL-c617t-e1519defee2c7b396e2bfe58489607f1174be6577e443459e9ee1e9db6c83d0f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/sj.gt.3302489$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/sj.gt.3302489$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=16872186$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15759018$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rutanen, J</creatorcontrib><creatorcontrib>Turunen, A-M</creatorcontrib><creatorcontrib>Teittinen, M</creatorcontrib><creatorcontrib>Rissanen, T T</creatorcontrib><creatorcontrib>Heikura, T</creatorcontrib><creatorcontrib>Koponen, J K</creatorcontrib><creatorcontrib>Gruchala, M</creatorcontrib><creatorcontrib>Inkala, M</creatorcontrib><creatorcontrib>Jauhiainen, S</creatorcontrib><creatorcontrib>Hiltunen, M O</creatorcontrib><creatorcontrib>Turunen, M P</creatorcontrib><creatorcontrib>Stacker, S A</creatorcontrib><creatorcontrib>Achen, M G</creatorcontrib><creatorcontrib>Ylä-Herttuala, S</creatorcontrib><title>Gene transfer using the mature form of VEGF-D reduces neointimal thickening through nitric oxide-dependent mechanism</title><title>Gene therapy</title><addtitle>Gene Ther</addtitle><addtitle>Gene Ther</addtitle><description>Gene transfer to the vessel wall using vascular endothelial growth factors (VEGFs) has shown therapeutic potential for the treatment of restenosis. In this study, we evaluated the effect of catheter-mediated adenoviral (Ad) gene transfer of the mature form of VEGF-D (VEGF-D ΔNΔC ) in balloon-denuded cholesterol-fed rabbit aorta. AdLacZ was used as a control. Transduced VEGF-D ΔNΔC mRNA was detectable in the arterial wall with RT-PCR at 6, 14 and 28 days. Gene transfer efficiency as detected with X-gal staining 6 days after the AdLacZ transduction was 1.91±1.32% in intima. AdVEGF-D ΔNΔC gene transfer led to 52% reduction in intima/media ratio (I/M) as compared to the AdLacZ controls at 14 days time point. At 6 days there were no differences in I/M, but the number of macrophages in the vessel wall was 85% lower in the AdVEGF-D ΔNΔC group as compared to the controls. The therapeutic effect was no longer detectable 28 days after the gene transfer. The therapeutic effect of VEGF-D ΔNΔC was nitric oxide (NO)-dependent as the feeding of NO synthase inhibitor, L -NAME, blocked the reduction in intimal thickening. It is concluded that AdVEGF-D ΔNΔC gene transfer reduces intimal thickening and macrophage influx into the vessel wall in balloon-denuded rabbit aortas.</description><subject>Adenoviridae - genetics</subject><subject>Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy</subject><subject>Animals</subject><subject>Aorta</subject><subject>Aortic Diseases - metabolism</subject><subject>Aortic Diseases - pathology</subject><subject>Aortic Diseases - therapy</subject><subject>Applied cell therapy and gene therapy</subject><subject>Biological and medical sciences</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Biotechnology</subject><subject>Care and treatment</subject><subject>Catheterization</subject><subject>Catheters</subject><subject>Cell Biology</subject><subject>Cholesterol</subject><subject>Constriction, Pathologic - therapy</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene Expression</subject><subject>Gene Therapy</subject><subject>Gene transfer</subject><subject>Genetic Therapy - methods</subject><subject>Genetic Vectors - administration &amp; dosage</subject><subject>Growth factors</subject><subject>Health aspects</subject><subject>Health. Pharmaceutical industry</subject><subject>Human Genetics</subject><subject>Industrial applications and implications. Economical aspects</subject><subject>Macrophages</subject><subject>Medical sciences</subject><subject>mRNA</subject><subject>Nanotechnology</subject><subject>Neovascularization, Pathologic</subject><subject>NG-Nitroarginine methyl ester</subject><subject>Nitric oxide</subject><subject>Nitric Oxide - metabolism</subject><subject>Nitric-oxide synthase</subject><subject>Physiological aspects</subject><subject>Polymerase chain reaction</subject><subject>Rabbits</subject><subject>Recurrence</subject><subject>research-article</subject><subject>Restenosis</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Risk factors</subject><subject>Stenosis</subject><subject>Transduction, Genetic - methods</subject><subject>Transfusions. Complications. Transfusion reactions. Cell and gene therapy</subject><subject>Tunica Intima - metabolism</subject><subject>Tunica Intima - pathology</subject><subject>Vascular endothelial growth factor</subject><subject>Vascular Endothelial Growth Factor D - genetics</subject><subject>Vascular Endothelial Growth Factor D - metabolism</subject><issn>0969-7128</issn><issn>1476-5462</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqF0suL1DAYAPAiijuuHr1KUFzw0DFp0zyOy7o7LiwIvq6hk37pZGyTMUlh_e_NMIVxZEVyKKS_L8n3KIqXBC8JrsX7uF32aVnXuKJCPioWhHJWNpRVj4sFlkyWnFTirHgW4xZjTLmonhZnpOGNxEQsirQCByiF1kUDAU3Ruh6lDaCxTVMAZHwYkTfo-_XqpvyAAnSThogceOuSHdshY6t_gDvEBT_1G-RsClYjf287KDvYgevAJTSC3rTOxvF58cS0Q4QX8_e8-HZz_fXqY3n3aXV7dXlXakZ4KoE0RHZgACrN17VkUK0NNCInyjA3hHC6BtZwDpTWtJEgAQjIbs20qDts6vPi4nDuLvifE8SkRhs1DEOb3z9FxbiQsmrYfyHhDZWU1Rm--Qtu_RRcTkJVjFJGcxf26vU_FRGMZ9gcj-rbAZR1xucu6P296pKISpAKE5rV8gGVVwej1d6BsXn_JODdSUA2Ce5T304xqtsvn0_txR92A-2QNtEPU7LexVNYHqAOPsYARu1Cbn74pQhW-zFUcav6pOYxzP7VXIBpPUJ31PPcZfB2Bm3U7WDy_Gkbj44Jvq_UMf2Yf7kewrGSD9_8G2fA8Y8</recordid><startdate>20050601</startdate><enddate>20050601</enddate><creator>Rutanen, J</creator><creator>Turunen, A-M</creator><creator>Teittinen, M</creator><creator>Rissanen, T T</creator><creator>Heikura, T</creator><creator>Koponen, J K</creator><creator>Gruchala, M</creator><creator>Inkala, M</creator><creator>Jauhiainen, S</creator><creator>Hiltunen, M O</creator><creator>Turunen, M P</creator><creator>Stacker, S A</creator><creator>Achen, M G</creator><creator>Ylä-Herttuala, S</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</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>ISR</scope><scope>3V.</scope><scope>7QP</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope><scope>7QO</scope><scope>7X8</scope></search><sort><creationdate>20050601</creationdate><title>Gene transfer using the mature form of VEGF-D reduces neointimal thickening through nitric oxide-dependent mechanism</title><author>Rutanen, J ; Turunen, A-M ; Teittinen, M ; Rissanen, T T ; Heikura, T ; Koponen, J K ; Gruchala, M ; Inkala, M ; Jauhiainen, S ; Hiltunen, M O ; Turunen, M P ; Stacker, S A ; Achen, M G ; Ylä-Herttuala, S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c617t-e1519defee2c7b396e2bfe58489607f1174be6577e443459e9ee1e9db6c83d0f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Adenoviridae - genetics</topic><topic>Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy</topic><topic>Animals</topic><topic>Aorta</topic><topic>Aortic Diseases - metabolism</topic><topic>Aortic Diseases - pathology</topic><topic>Aortic Diseases - therapy</topic><topic>Applied cell therapy and gene therapy</topic><topic>Biological and medical sciences</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Biotechnology</topic><topic>Care and treatment</topic><topic>Catheterization</topic><topic>Catheters</topic><topic>Cell Biology</topic><topic>Cholesterol</topic><topic>Constriction, Pathologic - therapy</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gene Expression</topic><topic>Gene Therapy</topic><topic>Gene transfer</topic><topic>Genetic Therapy - methods</topic><topic>Genetic Vectors - administration &amp; dosage</topic><topic>Growth factors</topic><topic>Health aspects</topic><topic>Health. 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subjects Adenoviridae - genetics
Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy
Animals
Aorta
Aortic Diseases - metabolism
Aortic Diseases - pathology
Aortic Diseases - therapy
Applied cell therapy and gene therapy
Biological and medical sciences
Biomedical and Life Sciences
Biomedicine
Biotechnology
Care and treatment
Catheterization
Catheters
Cell Biology
Cholesterol
Constriction, Pathologic - therapy
Fundamental and applied biological sciences. Psychology
Gene Expression
Gene Therapy
Gene transfer
Genetic Therapy - methods
Genetic Vectors - administration & dosage
Growth factors
Health aspects
Health. Pharmaceutical industry
Human Genetics
Industrial applications and implications. Economical aspects
Macrophages
Medical sciences
mRNA
Nanotechnology
Neovascularization, Pathologic
NG-Nitroarginine methyl ester
Nitric oxide
Nitric Oxide - metabolism
Nitric-oxide synthase
Physiological aspects
Polymerase chain reaction
Rabbits
Recurrence
research-article
Restenosis
Reverse Transcriptase Polymerase Chain Reaction
Risk factors
Stenosis
Transduction, Genetic - methods
Transfusions. Complications. Transfusion reactions. Cell and gene therapy
Tunica Intima - metabolism
Tunica Intima - pathology
Vascular endothelial growth factor
Vascular Endothelial Growth Factor D - genetics
Vascular Endothelial Growth Factor D - metabolism
title Gene transfer using the mature form of VEGF-D reduces neointimal thickening through nitric oxide-dependent mechanism
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