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Angiogenic response to extracorporeal shock wave treatment in murine skin isografts

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Abstract

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-1β, IL-6, G-CSF, VEGF-A), matrix metalloproteinases (MMP3, MMP9, MMP13), hypoxia-inducible factors (HIF-1α), 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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Abbreviations

ESWT:

Extracorporeal shock wave treatment

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Acknowledgments

This work was supported by ONR work unit 602236N.42237.W160.A0806 and by the Combat Wound Initiative Program, a Congressionally funded program of the Henry M. Jackson Foundation for the Advancement of Military Medicine.

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Authors and Affiliations

  1. Combat Wound Initiative Program, Department of Surgery, Walter Reed Army Medical Center, Washington, DC, USA

    Alexander Stojadinovic & Thomas A. Davis

  2. Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA

    Alexander Stojadinovic, Eric A. Elster & Douglas Tadaki

  3. Regenerative Medicine Department, Combat Casualty Care, Naval Medical Research Center, Room 2A10, 503 Robert Grant Avenue, Silver Spring, MD, 20910, USA

    Eric A. Elster, Khairul Anam, Douglas Tadaki, Mihret Amare, Stephen Zins & Thomas A. Davis

  4. Combat Wound Initiative Program, Department of Surgery, National Naval Medical Center, Bethesda, MD, USA

    Eric A. Elster

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  1. Alexander Stojadinovic
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Correspondence to Thomas A. Davis.

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The authors are employees of the U.S. Government. This work was prepared as part of their official duties. Title 17 U.S.C. §105 provides that ‘Copyright protection under this title is not available for any work of the U.S. Government’. Title 17 U.S.C. §101 defined a U.S. Government work as a work prepared by a military service member or employees of the U.S. Government as part of that person’s official duties. The opinions or assertions contained in this paper are the private views of the authors and are not to be construed as reflecting the views, policy or positions of the Department of the Navy or Army, Department of Defense nor the U.S. Government. The experiments reported herein were conducted in compliance with the Animal welfare Act and in accordance with the principles set forth in the current edition of the Guide for Care and Use of Laboratory Animals, Institute for Laboratory Animal Resources, National Research Council, National Academy Press, 1996.

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Stojadinovic, A., Elster, E.A., Anam, K. et al. Angiogenic response to extracorporeal shock wave treatment in murine skin isografts. Angiogenesis 11, 369–380 (2008). https://doi.org/10.1007/s10456-008-9120-6

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