Adenovirus-mediated VEGF121 gene transfer stimulates angiogenesis in normoperfused skeletal muscle and preserves tissue perfusion after induction of ischemia

Luis Henrique W Gowdak, Lioubov Poliakova, Xiaotong Wang, Imre Kovesdi, Kenneth W. Fishbein, Antonella Zacheo, Roberta Palumbo, Stefania Straino, Costanza Emanueli, Massimiliano Marrocco-Trischitta, Edward Lakatta, Piero Anversa, Richard G S Spencer, Mark Talan, Maurizio C. Capogrossi

Research output: Contribution to journalArticle

Abstract

Background - Administration of angiogenic factors stimulates neovascularization in ischemic tissues. However, there is no evidence that angiogenesis can be induced in normoperfused skeletal muscles. We tested the hypothesis that adenovirus-mediated intramuscular (IM) gene transfer of the 121-amino-acid form of vascular endothelial growth factor (AdCMV.VEGF121) could stimulate neovascularization in nonischemic skeletal muscle and consequently attenuate the hemodynamic deficit secondary to surgically induced ischemia. Methods and Results - Rabbits and rats received IM injections of AdCMV.VEGF121, AdCMV.Null or saline in the thigh, 4 weeks (rabbits) or 2 weeks (rats) before femoral artery removal in the injected limb. In unoperated rats, at the site of injection of AdCMV.VEGF121, we found 96% and 29% increases in length density of arterioles and capillaries, respectively. Increased tissue perfusion (TP) to the ischemic limb in the AdCMV.VEGF121 group was documented, as early as day 1 after surgery, by improved blood flow to the ischemic gastrocnemius muscle measured by radioactive microspheres (AdCMV.VEGF121 = 5.69 ± 0.40, AdCMV.Null = 2.97 ± 0.50 and saline = 2.78 ± 0.43 mL · min-1 · 100 g-1 P < 0.001), more angiographically recognizable collateral vessels (angioscore) (AdCMV.VEGF121 = 50.58 ± 1.48, AdCMV.Null = 29.08 ± 4.22, saline = 11.83 ± 1.90, P < 0.0001) and improvement of the bioenergetic reserve of the gastrocnemius muscle as assessed by 31P NMR spectroscopy. Follow-up studies showed that superior TP to the ischemic limb in the AdCMV.VEGF121 group persisted until it was equalized by spontaneous collateral vessel development in. untreated animals. Conclusions - IM administration of AdCMV.VEGF121 stimulates angiogenesis in normoperfused skeletal muscles, and the newly formed vessels preserve TP after induction of ischemia.

Original languageEnglish (US)
Pages (from-to)565-571
Number of pages7
JournalCirculation
Volume102
Issue number5
StatePublished - Aug 1 2000
Externally publishedYes

Fingerprint

Adenoviridae
Skeletal Muscle
Ischemia
Perfusion
Muscles
Extremities
Genes
Rabbits
Angiogenesis Inducing Agents
Intramuscular Injections
Arterioles
Femoral Artery
Thigh
Microspheres
Energy Metabolism
Vascular Endothelial Growth Factor A
Magnetic Resonance Spectroscopy
Hemodynamics
Amino Acids
Injections

Keywords

  • Angiogenesis
  • Endothelium-derived factors
  • Genes
  • Ischemia
  • Peripheral vascular disease

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Gowdak, L. H. W., Poliakova, L., Wang, X., Kovesdi, I., Fishbein, K. W., Zacheo, A., ... Capogrossi, M. C. (2000). Adenovirus-mediated VEGF121 gene transfer stimulates angiogenesis in normoperfused skeletal muscle and preserves tissue perfusion after induction of ischemia. Circulation, 102(5), 565-571.

Adenovirus-mediated VEGF121 gene transfer stimulates angiogenesis in normoperfused skeletal muscle and preserves tissue perfusion after induction of ischemia. / Gowdak, Luis Henrique W; Poliakova, Lioubov; Wang, Xiaotong; Kovesdi, Imre; Fishbein, Kenneth W.; Zacheo, Antonella; Palumbo, Roberta; Straino, Stefania; Emanueli, Costanza; Marrocco-Trischitta, Massimiliano; Lakatta, Edward; Anversa, Piero; Spencer, Richard G S; Talan, Mark; Capogrossi, Maurizio C.

In: Circulation, Vol. 102, No. 5, 01.08.2000, p. 565-571.

Research output: Contribution to journalArticle

Gowdak, LHW, Poliakova, L, Wang, X, Kovesdi, I, Fishbein, KW, Zacheo, A, Palumbo, R, Straino, S, Emanueli, C, Marrocco-Trischitta, M, Lakatta, E, Anversa, P, Spencer, RGS, Talan, M & Capogrossi, MC 2000, 'Adenovirus-mediated VEGF121 gene transfer stimulates angiogenesis in normoperfused skeletal muscle and preserves tissue perfusion after induction of ischemia', Circulation, vol. 102, no. 5, pp. 565-571.
Gowdak, Luis Henrique W ; Poliakova, Lioubov ; Wang, Xiaotong ; Kovesdi, Imre ; Fishbein, Kenneth W. ; Zacheo, Antonella ; Palumbo, Roberta ; Straino, Stefania ; Emanueli, Costanza ; Marrocco-Trischitta, Massimiliano ; Lakatta, Edward ; Anversa, Piero ; Spencer, Richard G S ; Talan, Mark ; Capogrossi, Maurizio C. / Adenovirus-mediated VEGF121 gene transfer stimulates angiogenesis in normoperfused skeletal muscle and preserves tissue perfusion after induction of ischemia. In: Circulation. 2000 ; Vol. 102, No. 5. pp. 565-571.
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abstract = "Background - Administration of angiogenic factors stimulates neovascularization in ischemic tissues. However, there is no evidence that angiogenesis can be induced in normoperfused skeletal muscles. We tested the hypothesis that adenovirus-mediated intramuscular (IM) gene transfer of the 121-amino-acid form of vascular endothelial growth factor (AdCMV.VEGF121) could stimulate neovascularization in nonischemic skeletal muscle and consequently attenuate the hemodynamic deficit secondary to surgically induced ischemia. Methods and Results - Rabbits and rats received IM injections of AdCMV.VEGF121, AdCMV.Null or saline in the thigh, 4 weeks (rabbits) or 2 weeks (rats) before femoral artery removal in the injected limb. In unoperated rats, at the site of injection of AdCMV.VEGF121, we found 96{\%} and 29{\%} increases in length density of arterioles and capillaries, respectively. Increased tissue perfusion (TP) to the ischemic limb in the AdCMV.VEGF121 group was documented, as early as day 1 after surgery, by improved blood flow to the ischemic gastrocnemius muscle measured by radioactive microspheres (AdCMV.VEGF121 = 5.69 ± 0.40, AdCMV.Null = 2.97 ± 0.50 and saline = 2.78 ± 0.43 mL · min-1 · 100 g-1 P < 0.001), more angiographically recognizable collateral vessels (angioscore) (AdCMV.VEGF121 = 50.58 ± 1.48, AdCMV.Null = 29.08 ± 4.22, saline = 11.83 ± 1.90, P < 0.0001) and improvement of the bioenergetic reserve of the gastrocnemius muscle as assessed by 31P NMR spectroscopy. Follow-up studies showed that superior TP to the ischemic limb in the AdCMV.VEGF121 group persisted until it was equalized by spontaneous collateral vessel development in. untreated animals. Conclusions - IM administration of AdCMV.VEGF121 stimulates angiogenesis in normoperfused skeletal muscles, and the newly formed vessels preserve TP after induction of ischemia.",
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TY - JOUR

T1 - Adenovirus-mediated VEGF121 gene transfer stimulates angiogenesis in normoperfused skeletal muscle and preserves tissue perfusion after induction of ischemia

AU - Gowdak, Luis Henrique W

AU - Poliakova, Lioubov

AU - Wang, Xiaotong

AU - Kovesdi, Imre

AU - Fishbein, Kenneth W.

AU - Zacheo, Antonella

AU - Palumbo, Roberta

AU - Straino, Stefania

AU - Emanueli, Costanza

AU - Marrocco-Trischitta, Massimiliano

AU - Lakatta, Edward

AU - Anversa, Piero

AU - Spencer, Richard G S

AU - Talan, Mark

AU - Capogrossi, Maurizio C.

PY - 2000/8/1

Y1 - 2000/8/1

N2 - Background - Administration of angiogenic factors stimulates neovascularization in ischemic tissues. However, there is no evidence that angiogenesis can be induced in normoperfused skeletal muscles. We tested the hypothesis that adenovirus-mediated intramuscular (IM) gene transfer of the 121-amino-acid form of vascular endothelial growth factor (AdCMV.VEGF121) could stimulate neovascularization in nonischemic skeletal muscle and consequently attenuate the hemodynamic deficit secondary to surgically induced ischemia. Methods and Results - Rabbits and rats received IM injections of AdCMV.VEGF121, AdCMV.Null or saline in the thigh, 4 weeks (rabbits) or 2 weeks (rats) before femoral artery removal in the injected limb. In unoperated rats, at the site of injection of AdCMV.VEGF121, we found 96% and 29% increases in length density of arterioles and capillaries, respectively. Increased tissue perfusion (TP) to the ischemic limb in the AdCMV.VEGF121 group was documented, as early as day 1 after surgery, by improved blood flow to the ischemic gastrocnemius muscle measured by radioactive microspheres (AdCMV.VEGF121 = 5.69 ± 0.40, AdCMV.Null = 2.97 ± 0.50 and saline = 2.78 ± 0.43 mL · min-1 · 100 g-1 P < 0.001), more angiographically recognizable collateral vessels (angioscore) (AdCMV.VEGF121 = 50.58 ± 1.48, AdCMV.Null = 29.08 ± 4.22, saline = 11.83 ± 1.90, P < 0.0001) and improvement of the bioenergetic reserve of the gastrocnemius muscle as assessed by 31P NMR spectroscopy. Follow-up studies showed that superior TP to the ischemic limb in the AdCMV.VEGF121 group persisted until it was equalized by spontaneous collateral vessel development in. untreated animals. Conclusions - IM administration of AdCMV.VEGF121 stimulates angiogenesis in normoperfused skeletal muscles, and the newly formed vessels preserve TP after induction of ischemia.

AB - Background - Administration of angiogenic factors stimulates neovascularization in ischemic tissues. However, there is no evidence that angiogenesis can be induced in normoperfused skeletal muscles. We tested the hypothesis that adenovirus-mediated intramuscular (IM) gene transfer of the 121-amino-acid form of vascular endothelial growth factor (AdCMV.VEGF121) could stimulate neovascularization in nonischemic skeletal muscle and consequently attenuate the hemodynamic deficit secondary to surgically induced ischemia. Methods and Results - Rabbits and rats received IM injections of AdCMV.VEGF121, AdCMV.Null or saline in the thigh, 4 weeks (rabbits) or 2 weeks (rats) before femoral artery removal in the injected limb. In unoperated rats, at the site of injection of AdCMV.VEGF121, we found 96% and 29% increases in length density of arterioles and capillaries, respectively. Increased tissue perfusion (TP) to the ischemic limb in the AdCMV.VEGF121 group was documented, as early as day 1 after surgery, by improved blood flow to the ischemic gastrocnemius muscle measured by radioactive microspheres (AdCMV.VEGF121 = 5.69 ± 0.40, AdCMV.Null = 2.97 ± 0.50 and saline = 2.78 ± 0.43 mL · min-1 · 100 g-1 P < 0.001), more angiographically recognizable collateral vessels (angioscore) (AdCMV.VEGF121 = 50.58 ± 1.48, AdCMV.Null = 29.08 ± 4.22, saline = 11.83 ± 1.90, P < 0.0001) and improvement of the bioenergetic reserve of the gastrocnemius muscle as assessed by 31P NMR spectroscopy. Follow-up studies showed that superior TP to the ischemic limb in the AdCMV.VEGF121 group persisted until it was equalized by spontaneous collateral vessel development in. untreated animals. Conclusions - IM administration of AdCMV.VEGF121 stimulates angiogenesis in normoperfused skeletal muscles, and the newly formed vessels preserve TP after induction of ischemia.

KW - Angiogenesis

KW - Endothelium-derived factors

KW - Genes

KW - Ischemia

KW - Peripheral vascular disease

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