Low‐energy extracorporeal shock wave therapy enhances skin wound healing in diabetic mice: A critical role of endothelial nitric oxide synthase

Abstract

Low-energy extracorporeal shock wave (LE-ESW) treatment has been shown to accelerate wound repair; however, the mechanisms of treatment remain unclear. In the present study, we addressed the role of endothelial nitric oxide synthase (eNOS). A single LE-ESW treatment accelerated the healing of wounds in diabetic mice caused by the injection of streptozotocin. This accelerated healing was accompanied by the increased expression of eNOS and vascular endothelial growth factor (VEGF) and the generation of new vessels at the wound tissues. These results raised the possibility that eNOS may be involved in the beneficial effects of LE-ESW treatment. To address this possibility, we compared the effects of this treatment between mice with a genetic disruption of eNOS knockout (eNOS-KO mice) and wild-type (WT) control mice. Interestingly, the LE-ESW-induced acceleration of wound closure and the increase in VEGF expression and neovascularization was significantly attenuated in eNOS-KO mice compared with WT mice. Considered collectively, these results showed that eNOS was induced at the wound tissues by LE-ESW treatment and played a critical role in the therapeutic effects of this treatment by accelerating the wound healing by promoting VEGF expression and neovascularization.

Shock Wave Treatment Enhances Cell Proliferation and Improves Wound Healing by ATP Release-coupled Extracellular Signal-regulated Kinase (ERK) Activation

“…of ESWT, namely its ability to induce the healing of chronic ulcers and non-healing wounds (1)(2)(3)(4)(5).…”

“…A standard rodent ischemic epigastric flap model was modified to study the effect of shock wave treatment on ischemia-impaired wound healing (37). 4 In brief, rats were anesthetized in an inhalation box using isoflurane (2.5 volume %). Anesthesia was maintained by intraperitoneal injection of a mixture of ketamine (110 mg/kg; Pharmacia and Upjohn, Germany) and xylazine (12 mg/kg; Bayer, Leverkusen, Germany).…”

“…In addition to the accelerated healing rates in patients treated with ESWT, this therapeutic approach is noninvasive and cost-effective. Despite the growing evidence of the beneficial clinical effects of ESWT in treating musculoskeletal disorders and soft tissue wounds in animal models and clinical studies (3)(4)(5)(6)(7)(8)(9)(10), the underlying mechanisms of how ESWT exerts these beneficial effects have remained unclear.…”

“…In recent years, various research groups have focused on the angiogenic impact of shock waves (4,5,12,13). They have shown that ESWT up-regulates angiogenesis via mediators such as vascular endothelial growth factor (VEGF), endothelial nitric-oxide synthase, hypoxia-inducible factor 1a, and CD31 (4,5,14,15). ESWT was shown to augment the expression of proliferating cell nuclear antigen and the recruitment of fibroblasts and to down-regulate production of proinflammatory cytokines (16).…”

Extracorporeal Shock Wave Therapy for Digital Ulcers of Systemic Sclerosis: A Phase 2 Pilot Study

“…The efficacy and safety of ESWT for patients with angina pectoris has also been reported (Fukumoto et al 2006;Kikuchi et al 2010). Moreover, Hayashi et al (2012) reported that endothelial nitric oxide synthase played a critical role in ESWT-induced accelerated wound healing in diabetic mice by promoting VEGF expression and neovascularization. Clinically, Moretti et al (2009) reported, in a controlled study, that ESWT was effective in curing and reepithelialization of diabetic neuropathic foot ulcers.…”