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.

Objective Angiotensin II (Ang II), a potent vasoconstrictor, affects the growth and development of hematopoietic cells. Mixed findings have been reported for the effects of ACE inhibitors on radiation-induced injury to the hematopoietic system. We investigated the consequences of different regimens of the ACE inhibitor captopril on radiation-induced hematopoietic injury. Methods C57BL/6 mice were either sham irradiated or were exposed to 60Co total body irradiation (0.6 Gy/min). Captopril was provided in the water for different time periods relative to irradiation. Results In untreated mice, the survival rate from 7.5 Gy was 50% at 30 days postirradiation. Captopril treatment for 7 days prior to irradiation resulted in radiosensitization with 100% lethality and a rapid decline of mature blood cells. In contrast, captopril treatment beginning 1 hour postirradiation and continuing for 30 days resulted in 100% survival, with improved recovery of mature blood cells and multilineage hematopoietic progenitors. In nonirradiated control mice captopril biphasically modulated Lin− marrow progenitor cell cycling. After 2 days, captopril suppressed G0-G1 transition and a greater number of cells entered a quiescent state. However, after 7 days of captopril treatment Linprogenitor cell cycling increased compared to untreated control mice. Conclusion These findings suggest that ACE inhibition affects hematopoietic recovery following radiation by modulating the hematopoietic progenitor cell cycle. The timing of captopril treatment relative to radiation exposure differentially affects the viability and repopulation capacity of spared hematopoietic stem cells and therefore can result in either radiation protection or radiation sensitization.

Pretreatment with genistein provides in vivo protection from acute myelotoxicity through extended quiescence followed by reduced senescence of marrow repopulating LSK(+).

Impaired wound healing is a persistent clinical problem which has been treated with mixed results. Studies aimed at elucidating the mechanism of impaired wound healing have focused on small cohorts of genes which leave an incomplete picture of the wound healing process. We aimed to investigate impaired wound healing via a comprehensive panel of angiogenic/inflammation-related genes and wound closure kinetics with and without the application of extracorporeal shock wave therapy (ESWT), which has been demonstrated to improve wound healing. Full-thickness skin from the dorsal surface of "normal" (BALB/c) and "impaired" (db (+)/db (+)) mice was excised, and wound margin tissue was harvested 2, 7, and 10 days post injury. A separate, but identical wound model was established over 40 days in order to measure wound closure kinetics. Over time, the normal non-ESWT treated wounds exhibited varying patterns of elevated expression of 25-30 genes, whereas wounds with impaired healing displayed prolonged elevated expression of only a few genes (CXCL2, CXCL5, CSF3, MMP9, TGF-α). In response to ESWT, gene expression was augmented in both types of wounds, especially in the expression of PECAM-1; however, ESWT had no effect on wound closure in either model. In addition, multiple doses of ESWT exacerbated the delayed wound healing, and actually caused the wounds to initially increase in size. These data provide a more complete picture of impaired wound healing, and a way to evaluate various promising treatments.

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