Local gene transfer of phVEGF-2 plasmid by gene-eluting stents

An alternative strategy for inhibition of restenosis

Dirk H. Walter, Manfred Cejna, Larry Diaz-Sandoval, Sean Willis, Laura Kirkwood, Peter W. Stratford, Anne B. Tietz, Rudolf Kirchmair, Marcy Silver, Cindy Curry, Andrea Wecker, Youngsup Yoon, Regina Heidenreich, Allison Hanley, Marianne Kearney, Fermin O. Tio, Patrik Kuenzler, Jeffrey M. Isner, Douglas W. Losordo

Research output: Contribution to journalArticle

182 Citations (Scopus)

Abstract

Background - Drug-eluting stents represent a useful strategy for the prevention of restenosis using various antiproliferative drugs. These strategies share the liability of impairing endothelial recovery, thereby altering the natural biology of the vessel wall and increasing the associated risk of stent thrombosis. Accordingly, we tested the hypothesis that local delivery via gene-eluting stent of naked plasmid DNA encoding for human vascular endothelial growth factor (VEGF)-2 could achieve similar reductions in neointima formation while accelerating, rather than inhibiting, reendothelialization. Methods and Results - phVEGF 2-plasmid (100 or 200 μg per stent)-coated BiodivYsio phosphorylcholine polymer stents versus uncoated stents were deployed in a randomized, blinded fashion in iliac arteries of 40 normocholesterolemic and 16 hypercholesterolemic rabbits. Reendothelialization was nearly complete in the VEGF stent group after 10 days and was significantly greater than in control stents (98.7±1% versus 79.0±6%, P<0.01). At 3 months, intravascular ultrasound analysis revealed that lumen cross-sectional area (4.2±0.4 versus 2.27±0.3 mm2, P<0.001) was significantly greater and percent cross-sectional narrowing was significantly lower (23.4±6 versus 51.2±10, P<0.001) in VEGF stents compared with control stents implanted in hypercholesterolemic rabbits. Transgene expression was detectable in the vessel wall along with improved functional recovery of stented segments, resulting in a 2.4-fold increase in NO production. Conclusions - Acceleration of reendothelialization via VEGF-2 gene-eluting stents provides an alternative treatment strategy for the prevention of restenosis. VEGF-2 gene-eluting stents may be considered as a stand-alone or combination therapy.

Original languageEnglish
Pages (from-to)36-45
Number of pages10
JournalCirculation
Volume110
Issue number1
DOIs
Publication statusPublished - 2004 Jul 6

Fingerprint

Stents
Plasmids
Genes
Vascular Endothelial Growth Factor A
Rabbits
Neointima
Drug-Eluting Stents
Phosphorylcholine
Iliac Artery
Transgenes
Polymers
Thrombosis
DNA

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Walter, D. H., Cejna, M., Diaz-Sandoval, L., Willis, S., Kirkwood, L., Stratford, P. W., ... Losordo, D. W. (2004). Local gene transfer of phVEGF-2 plasmid by gene-eluting stents: An alternative strategy for inhibition of restenosis. Circulation, 110(1), 36-45. https://doi.org/10.1161/01.CIR.0000133324.38115.0A
Walter, Dirk H. ; Cejna, Manfred ; Diaz-Sandoval, Larry ; Willis, Sean ; Kirkwood, Laura ; Stratford, Peter W. ; Tietz, Anne B. ; Kirchmair, Rudolf ; Silver, Marcy ; Curry, Cindy ; Wecker, Andrea ; Yoon, Youngsup ; Heidenreich, Regina ; Hanley, Allison ; Kearney, Marianne ; Tio, Fermin O. ; Kuenzler, Patrik ; Isner, Jeffrey M. ; Losordo, Douglas W. / Local gene transfer of phVEGF-2 plasmid by gene-eluting stents : An alternative strategy for inhibition of restenosis. In: Circulation. 2004 ; Vol. 110, No. 1. pp. 36-45.
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abstract = "Background - Drug-eluting stents represent a useful strategy for the prevention of restenosis using various antiproliferative drugs. These strategies share the liability of impairing endothelial recovery, thereby altering the natural biology of the vessel wall and increasing the associated risk of stent thrombosis. Accordingly, we tested the hypothesis that local delivery via gene-eluting stent of naked plasmid DNA encoding for human vascular endothelial growth factor (VEGF)-2 could achieve similar reductions in neointima formation while accelerating, rather than inhibiting, reendothelialization. Methods and Results - phVEGF 2-plasmid (100 or 200 μg per stent)-coated BiodivYsio phosphorylcholine polymer stents versus uncoated stents were deployed in a randomized, blinded fashion in iliac arteries of 40 normocholesterolemic and 16 hypercholesterolemic rabbits. Reendothelialization was nearly complete in the VEGF stent group after 10 days and was significantly greater than in control stents (98.7±1{\%} versus 79.0±6{\%}, P<0.01). At 3 months, intravascular ultrasound analysis revealed that lumen cross-sectional area (4.2±0.4 versus 2.27±0.3 mm2, P<0.001) was significantly greater and percent cross-sectional narrowing was significantly lower (23.4±6 versus 51.2±10, P<0.001) in VEGF stents compared with control stents implanted in hypercholesterolemic rabbits. Transgene expression was detectable in the vessel wall along with improved functional recovery of stented segments, resulting in a 2.4-fold increase in NO production. Conclusions - Acceleration of reendothelialization via VEGF-2 gene-eluting stents provides an alternative treatment strategy for the prevention of restenosis. VEGF-2 gene-eluting stents may be considered as a stand-alone or combination therapy.",
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Walter, DH, Cejna, M, Diaz-Sandoval, L, Willis, S, Kirkwood, L, Stratford, PW, Tietz, AB, Kirchmair, R, Silver, M, Curry, C, Wecker, A, Yoon, Y, Heidenreich, R, Hanley, A, Kearney, M, Tio, FO, Kuenzler, P, Isner, JM & Losordo, DW 2004, 'Local gene transfer of phVEGF-2 plasmid by gene-eluting stents: An alternative strategy for inhibition of restenosis', Circulation, vol. 110, no. 1, pp. 36-45. https://doi.org/10.1161/01.CIR.0000133324.38115.0A

Local gene transfer of phVEGF-2 plasmid by gene-eluting stents : An alternative strategy for inhibition of restenosis. / Walter, Dirk H.; Cejna, Manfred; Diaz-Sandoval, Larry; Willis, Sean; Kirkwood, Laura; Stratford, Peter W.; Tietz, Anne B.; Kirchmair, Rudolf; Silver, Marcy; Curry, Cindy; Wecker, Andrea; Yoon, Youngsup; Heidenreich, Regina; Hanley, Allison; Kearney, Marianne; Tio, Fermin O.; Kuenzler, Patrik; Isner, Jeffrey M.; Losordo, Douglas W.

In: Circulation, Vol. 110, No. 1, 06.07.2004, p. 36-45.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Local gene transfer of phVEGF-2 plasmid by gene-eluting stents

T2 - An alternative strategy for inhibition of restenosis

AU - Walter, Dirk H.

AU - Cejna, Manfred

AU - Diaz-Sandoval, Larry

AU - Willis, Sean

AU - Kirkwood, Laura

AU - Stratford, Peter W.

AU - Tietz, Anne B.

AU - Kirchmair, Rudolf

AU - Silver, Marcy

AU - Curry, Cindy

AU - Wecker, Andrea

AU - Yoon, Youngsup

AU - Heidenreich, Regina

AU - Hanley, Allison

AU - Kearney, Marianne

AU - Tio, Fermin O.

AU - Kuenzler, Patrik

AU - Isner, Jeffrey M.

AU - Losordo, Douglas W.

PY - 2004/7/6

Y1 - 2004/7/6

N2 - Background - Drug-eluting stents represent a useful strategy for the prevention of restenosis using various antiproliferative drugs. These strategies share the liability of impairing endothelial recovery, thereby altering the natural biology of the vessel wall and increasing the associated risk of stent thrombosis. Accordingly, we tested the hypothesis that local delivery via gene-eluting stent of naked plasmid DNA encoding for human vascular endothelial growth factor (VEGF)-2 could achieve similar reductions in neointima formation while accelerating, rather than inhibiting, reendothelialization. Methods and Results - phVEGF 2-plasmid (100 or 200 μg per stent)-coated BiodivYsio phosphorylcholine polymer stents versus uncoated stents were deployed in a randomized, blinded fashion in iliac arteries of 40 normocholesterolemic and 16 hypercholesterolemic rabbits. Reendothelialization was nearly complete in the VEGF stent group after 10 days and was significantly greater than in control stents (98.7±1% versus 79.0±6%, P<0.01). At 3 months, intravascular ultrasound analysis revealed that lumen cross-sectional area (4.2±0.4 versus 2.27±0.3 mm2, P<0.001) was significantly greater and percent cross-sectional narrowing was significantly lower (23.4±6 versus 51.2±10, P<0.001) in VEGF stents compared with control stents implanted in hypercholesterolemic rabbits. Transgene expression was detectable in the vessel wall along with improved functional recovery of stented segments, resulting in a 2.4-fold increase in NO production. Conclusions - Acceleration of reendothelialization via VEGF-2 gene-eluting stents provides an alternative treatment strategy for the prevention of restenosis. VEGF-2 gene-eluting stents may be considered as a stand-alone or combination therapy.

AB - Background - Drug-eluting stents represent a useful strategy for the prevention of restenosis using various antiproliferative drugs. These strategies share the liability of impairing endothelial recovery, thereby altering the natural biology of the vessel wall and increasing the associated risk of stent thrombosis. Accordingly, we tested the hypothesis that local delivery via gene-eluting stent of naked plasmid DNA encoding for human vascular endothelial growth factor (VEGF)-2 could achieve similar reductions in neointima formation while accelerating, rather than inhibiting, reendothelialization. Methods and Results - phVEGF 2-plasmid (100 or 200 μg per stent)-coated BiodivYsio phosphorylcholine polymer stents versus uncoated stents were deployed in a randomized, blinded fashion in iliac arteries of 40 normocholesterolemic and 16 hypercholesterolemic rabbits. Reendothelialization was nearly complete in the VEGF stent group after 10 days and was significantly greater than in control stents (98.7±1% versus 79.0±6%, P<0.01). At 3 months, intravascular ultrasound analysis revealed that lumen cross-sectional area (4.2±0.4 versus 2.27±0.3 mm2, P<0.001) was significantly greater and percent cross-sectional narrowing was significantly lower (23.4±6 versus 51.2±10, P<0.001) in VEGF stents compared with control stents implanted in hypercholesterolemic rabbits. Transgene expression was detectable in the vessel wall along with improved functional recovery of stented segments, resulting in a 2.4-fold increase in NO production. Conclusions - Acceleration of reendothelialization via VEGF-2 gene-eluting stents provides an alternative treatment strategy for the prevention of restenosis. VEGF-2 gene-eluting stents may be considered as a stand-alone or combination therapy.

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U2 - 10.1161/01.CIR.0000133324.38115.0A

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