Synergistic effect of vascular endothelial growth factor and granulocyte colony‐stimulating factor double gene therapy in mouse limb ischemia

Sacramento, Chester Bittencourt; Silva, Flávia Helena da; Nardi, Nance Beyer; Yasumura, Eduardo Gallatti; Baptista-Silva, José Carlos Costa; Beutel, Abram; Campos, Rui; Moraes, Jane Zveiter de; Silva, Hamilton; Samoto, Vívian Yochiko; Borojević, Radovan; Han, Sang Won

doi:10.1002/jgm.1434

Cited by 20 publications

(18 citation statements)

References 50 publications

(47 reference statements)

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“…In most of the animal studies, vectors expressing VEGF have been injected directly into the ischemic tissue, and this was found to improve blood flux and transiently augment vessel density [2]. However, we and other groups have demonstrated that long periods of high expression of this gene in ischemic tissue can lead to deleterious effects, such as a decrease in capillary density, the loss of muscle mass and force and the augmentation of limb necrosis [27], [30], [31]. It is likely that the high concentration of VEGF provided by the ischemic tissues together with the transfected cells promotes fast endothelial cell proliferation and vessel formation, which are not followed by adequate vessel maturation.…”

Section: Discussionmentioning

confidence: 99%

“…These premature vessels in muscles can be easily disassembled by muscular movements, potentially leading to edema and cell death. Using VEGF together with either the stem cell mobilizing factor G-CSF (granulocyte colony stimulating factor) or the arteriogenic and vasculogenic factor GM-CSF (granulocyte macrophage-colony stimulating factor) to treat mouse ischemic limbs has resulted in much better outcomes than treatment with VEGF alone [26], [27]. Our interpretation of these results is that, to make a stable and functional vessel, it is necessary to recruit more growth factors and cells in an adequate time frame and at adequate concentrations, as happens physiologically.…”

Section: Discussionmentioning

confidence: 99%

“…Initially, 10–12 week-old Balb/c male mice were anesthetized with an intraperitoneal injection of ketamine (40 mg/kg) and xylazine (20 mg/kg). Hind limb ischemia was induced surgically as previously described [26], [27]. Briefly, the femoral artery was excised from its origin at the external iliac artery branch to its bifurcation into the saphenous and popliteal arteries without damaging the femoralis vein or nerves.…”

Section: Methodsmentioning

confidence: 99%

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Treatment of Mouse Limb Ischemia with an Integrative Hypoxia-Responsive Vector Expressing the Vascular Endothelial Growth Factor Gene

Yasumura¹,

Stilhano²,

Samoto³

et al. 2012

PLoS ONE

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Constitutive vascular endothelial growth factor (VEGF) gene expression systems have been extensively used to treat peripheral arterial diseases, but most of the results have not been satisfactory. In this study, we designed a plasmid vector with a hypoxia-responsive element sequence incorporated into it with the phiC31 integrative system (pVHAVI) to allow long-term VEGF gene expression and to be activated under hypoxia. Repeated activations of VEGF gene expression under hypoxia were confirmed in HEK293 and C2C12 cells transfected with pVHAVI. In limb ischemic mice, the local administration of pVHAVI promoted gastrocnemius mass and force recovery and ameliorated limb necrosis much better than the group treated with hypoxia-insensitive vector, even this last group had produced more VEGF in muscle. Histological analyses carried out after four weeks of gene therapy showed increased capillary density and matured vessels, and reduced number of necrotic cells and fibrosis in pVHAVI treated group. By our study, we demonstrate that the presence of high concentration of VEGF in ischemic tissue is not beneficial or is less beneficial than maintaining a lower but sufficient and long-term concentration of VEGF locally.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Treatment of Mouse Limb Ischemia with an Integrative Hypoxia-Responsive Vector Expressing the Vascular Endothelial Growth Factor Gene

Yasumura¹,

Stilhano²,

Samoto³

et al. 2012

PLoS ONE

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“…In this study, a multi-electrode array was used to deliver plasmid DNA to the skin [35]. In another study, VEGF and stem cell mobilizer granulocyte colony-stimulating factor (G-CSF) genes were transferred to mouse ischemic limbs by electroporation [92] and this double gene therapy showed a synergistic effect leading to vessel and tissue repair in hind limb ischemia.…”

Section: Peripheral Artery Diseasementioning

confidence: 99%

Plasmid DNA Gene Therapy by Electroporation: Principles and Recent Advances

Murakami

Sunada²

2011

CGT

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Simple plasmid DNA injection is a safe and feasible gene transfer method, but it confers low transfection efficiency and transgene expression. This non-viral gene transfer method is enhanced by physical delivery methods, such as electroporation and the use of a gene gun. In vivo electroporation has been rapidly developed over the last two decades to deliver DNA to various tissues or organs. It is generally considered that membrane permeabilization and DNA electrophoresis play important roles in electro-gene transfer. Skeletal muscle is a well characterized target tissue for electroporation, because it is accessible and allows for long-lasting gene expression ( > one year). Skin is also a target tissue because of its accessibility and immunogenicity. Numerous studies have been performed using in vivo electroporation in animal models of disease. Clinical trials of DNA vaccines and immunotherapy for cancer treatment using in vivo electroporation have been initiated in patients with melanoma and prostate cancer. Furthermore, electroporation has been applied to DNA vaccines for infectious diseases to enhance immunogenicity, and the relevant clinical trials have been initiated. The gene gun approach is also being applied for the delivery of DNA vaccines against infectious diseases to the skin. Here, we review recent advances in the mechanism of in vivo electroporation, and summarize the findings of recent preclinical and clinical studies using this technology.

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“…The synergistic effect of VEGF and granulocyte-colony stimulating factor (G-CSF) was tested in a mouse limb ischemia model. There was a distinct reduction of the level of necrosis in the group treated with VEGF and G-CSF compared with the untreated ischemic group [29], which underlines the antifibrotic effect. Another study [3] showed that local and sustained release of VEGF from macroporous scaffolds used to transplant and disperse cultured myogenic cells limited fibrosis and accelerated the regenerative process.…”

Section: Discussionmentioning

confidence: 68%

VEGF Improves Skeletal Muscle Regeneration After Acute Trauma and Reconstruction of the Limb in a Rabbit Model

Frey

Jansen

Raschke

et al. 2012

Clinical Orthopaedics &Amp; Related Research

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Background Complicated tibial fractures with severe soft tissue trauma are challenging to treat. Frequently associated acute compartment syndrome can result in scarring of muscles with impaired function. Several studies have shown a relationship between angiogenesis and more effective muscle regeneration. Vascular endothelial growth factor (VEGF) is associated with angiogenesis but it is not clear whether it would restore muscle force, reduce scarring, and aid in muscle regeneration after acute musculoskeletal trauma.

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Synergistic effect of vascular endothelial growth factor and granulocyte colony‐stimulating factor double gene therapy in mouse limb ischemia

Abstract: Gene therapy using VEGF and G-CSF demonstrated a synergistic effect promoting vessel and tissue repair in mouse hind limb ischemia.

Cited by 20 publications

References 50 publications

Treatment of Mouse Limb Ischemia with an Integrative Hypoxia-Responsive Vector Expressing the Vascular Endothelial Growth Factor Gene

Treatment of Mouse Limb Ischemia with an Integrative Hypoxia-Responsive Vector Expressing the Vascular Endothelial Growth Factor Gene

Plasmid DNA Gene Therapy by Electroporation: Principles and Recent Advances

VEGF Improves Skeletal Muscle Regeneration After Acute Trauma and Reconstruction of the Limb in a Rabbit Model

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