Adenovirus-mediated transforming growth factor-β ameliorates ischemic necrosis of epigastric skin flaps in a rat model1, 2

Huemer, Georg M.; Shafighi, Maziar; Meirer, Romed; Debagge, Paul; Piza‐Katzer, Hildegunde; Gürünlüoğlu, Raffi

doi:10.1016/j.jss.2004.02.012

Cited by 23 publications

(17 citation statements)

References 33 publications

(39 reference statements)

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“…Topical growth factor and cytokine therapy involving single pro-angiogenic proteins as well as adenovirus-mediated VEGF, TGF-b1, and angiopoietin-1 gene therapy have had partial therapeutic neoangiogenic effects in ischemic flaps and grafts [15,16,[33][34][35][36][37]. In an effort to improve the therapeutic index, biomechanical approaches using noninvasive modalities have been utilized to stimulate angiogenesis in ischemic tissue.…”

Section: Discussionmentioning

confidence: 99%

Angiogenic response to extracorporeal shock wave treatment in murine skin isografts

et al. 2008

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Skin grafts are commonly utilized and proven effective methods of open wound coverage. Revascularization through neoangiogenesis is a pivotal mechanism for skin graft integration and durability. Extracorporeal shock-wave treatment (ESWT) has been demonstrated to accelerate wound repair; however, its mechanism-of-action is unclear. We investigated the role of ESWT in early revascularization of full-thickness skin isografts in a murine model. Cohorts of mice were euthanized and skin grafts were harvested 6 h, 2, 4, and 7 days post grafting +/- ESWT. Various aspects of graft neovascularization were measured including gross morphology, quantitative microscopy (vessel number, density), immunohistochemistry (CD31), cDNA SuperArrays for 84 angiogenesis-specific genes, and custom-designed 'Wound Repair' TaqMan Low Density Array (TLDA) cards to assess expression of 188 wound repair genes. We demonstrate that a single administration of ESWT immediately following skin grafting significantly enhances recipient graft revascularization (increased vessel number, size, and density). An augmented early pro-angiogenic and suppressed delayed pro-inflammatory response to ESWT was accompanied by significantly increased expression of both skin graft CD31 and angiogenesis pathway-specific genes, including ELR-CXC chemokines (CXCL1, CXCL2, CXCL5), CC chemokines (CCL2, CCL3, CCL4), cytokines (IL-1 beta, IL-6, G-CSF, VEGF-A), matrix metalloproteinases (MMP3, MMP9, MMP13), hypoxia-inducible factors (HIF-1 alpha), and vascular remodeling kinase (Mst1), as early as 6 h and up to 7 days post grafting and treatment. These findings suggest that early pro-angiogenic and anti-inflammatory effects of ESWT promote tissue revascularization and wound healing by augmenting angiogenesis and dampening inflammation.

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Section: Discussionmentioning

confidence: 99%

Angiogenic response to extracorporeal shock wave treatment in murine skin isografts

et al. 2008

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“…8,9 However, no single pharmacological intervention has proven consistently effective. Novel approaches to therapeutic neovascularization are being evaluated currently including adenovirus-mediated transforming growth factor-β, vascular endothelial growth factor (VEGF), and angiopoietin-1 gene therapy; [10][11][12][13][14] fibroblast growth factor-2 delivery by encapsulated genetically engineered myoblasts; 15 and, transplantation of endothelial progenitor cells from human cord blood transfected with the VEGF gene. 16 The cost, complexity and associated risk of these targeted interventions limit widespread utilization aimed at confronting the formidable challenge in wound care and reconstructive surgery, that of ischemic necrosis in distal regions of composite flaps.…”

mentioning

confidence: 99%

Extracorporeal Shock Wave Therapy (ESWT) Minimizes Ischemic Tissue Necrosis Irrespective of Application Time and Promotes Tissue Revascularization by Stimulating Angiogenesis

et al. 2011

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“…There was no unexpected animal death or any detrimental inflammatory reaction resulting from adenovirus-mediated gene therapy, which was consistent with our previous studies. 25,26,37À39 However, our findings remain inadequate for assessing the long-term safety of virus vectors, because this was not a chronic toxicity study.…”

Section: Discussionmentioning

confidence: 99%

Gene therapy with adenovirus-mediated VEGF enhances skin flap prefabrication

Gürünlüoğlu

Meirer²,

Shafighi³

et al. 2005

Microsurgery

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We investigated the feasibility in rats of enhancing skin-flap prefabrication with subdermal injections of adenovirus-encoding vascular endothelial growth factor (Ad-VEGF). The left saphenous vascular pedicle was used as a source for vascular induction. A peninsular abdominal flap (8 x 8 cm) was elevated as distally based, keeping the epigastric vessels intact on both sides. After the vascular pedicle was tacked underneath the abdominal flap, 34 rats were randomly divided into three groups according to treatment protocol. The implantation site around the pedicle was injected with Ad-VEGF in group I (n = 10), with adenovirus-encoding green fluorescent protein (Ad-GFP) in control group I (n = 14), and with saline in control group II (n = 10). All injections were given subdermally at four points around the implanted vessel by an individual blinded to the treatment protocol. The peninsular flap was sutured in its place, and 4 weeks later, an abdominal island flap based solely on the implanted vessels was elevated. The prefabricated island flap was sutured back, and flap viability was evaluated on day 7. Skin specimens were stained with hematoxylin and eosin for histological evaluation. In two rats from each group, microangiography was performed to visualize the vascularity of the prefabricated flaps. There was a significant increase in survival of prefabricated flaps in the Ad-VEGF group compared to the control groups: Ad-VEGF, 88.9 +/- 6.1% vs. Ad-GFP, 65.6 +/- 9.4% (P < 0.05) and saline, 56.0 +/- 3.4% (P < 0.05). Sections from four prefabricated flaps treated with Ad-GFP revealed multiple sites of shiny deposits of green fluorescent protein around the area of local administration 1 day and 3 weeks after gene therapy. Histological examination done under high-power magnification (x400) with a light microscope revealed increased vascularity and mild inflammation surrounding the implanted vessel in all groups. However, we were unable to demonstrate any significant quantitative difference with respect to vascularity and inflammatory infiltrates in prefabricated flaps treated with Ad-VEGF compared with controls. Microangiographic studies showed increased vascularity around the implanted pedicle, which was similar in all groups. However, vascularization was distributed in a larger area in the prefabricated flaps treated with Ad-VEGF. In this study, the authors demonstrated that adenovirus-mediated VEGF gene therapy increased the survival of prefabricated flaps, suggesting that it may allow prefabrication of larger flaps and have the potential to reduce the time required for flap maturation.

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Adenovirus-mediated transforming growth factor-β ameliorates ischemic necrosis of epigastric skin flaps in a rat model1, 2

Cited by 23 publications

References 33 publications

Angiogenic response to extracorporeal shock wave treatment in murine skin isografts

Angiogenic response to extracorporeal shock wave treatment in murine skin isografts

Extracorporeal Shock Wave Therapy (ESWT) Minimizes Ischemic Tissue Necrosis Irrespective of Application Time and Promotes Tissue Revascularization by Stimulating Angiogenesis

Gene therapy with adenovirus-mediated VEGF enhances skin flap prefabrication

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