title: Angiogenic response to extracorporeal shock wave treatment in murine skin isografts.
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-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.
authors.affiliation: Combat Wound Initiative Program, Department of Surgery, Walter Reed Army Medical Center, Washington, DC, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Stojadinovic
authors.forename: Eric A
authors.initials: EA
authors.lastname: Elster
authors.forename: Khairul
authors.initials: K
authors.lastname: Anam
authors.forename: Douglas
authors.initials: D
authors.lastname: Tadaki
authors.forename: Mihret
authors.initials: M
authors.lastname: Amare
authors.forename: Stephen
authors.initials: S
authors.lastname: Zins
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Davis
mesh_terms: D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D005786:Gene Expression Regulation; D019220:High-Energy Shock Waves; D007150:Immunohistochemistry; D007511:Ischemia; D051379:Mice; D008807:Mice, Inbred BALB C; D018919:Neovascularization, Physiologic; D012867:Skin / Q000098:blood supply* / Q000166:cytology / Q000378:metabolism; D016038:Skin Transplantation; D014185:Transplantation, Isogeneic; D014945:Wound Healing / Q000235:genetics
chemical_list: D042501:Angiogenic Proteins