Abstract
Low-intensity extracorporeal shock wave therapy (Li-ESWT) is a form of energy transfer that is of lower intensity (<0.2mJ/mm2) relative to traditional Extracorporeal Shock Wave Lithotripsy (ESWL) used for management of urinary stones. At this intensity and at appropriate dosing energy transfer is thought to induce beneficial effects in human tissues. The proposed therapeutic mechanisms of action for Li-ESWT include neovascularization, tissue regeneration, and reduction of inflammation. These effects are thought to be mediated by enhanced expression of vascular endothelial growth factor, endothelial nitric oxide synthase, and proliferating cell nuclear antigen. Upregulation of chemoattractant factors and recruitment/activation of stem/progenitor cells may also play a role. Li-ESWT has been studied for management of musculoskeletal disease, ischemic cardiovascular disorders, Peyronie’s Disease, and more recently erectile dysfunction (ED). The underlying mechanism of Li-ESWT for treatment of ED is incompletely understood. We summarize the current evidence basis by which Li-ESWT is thought to enhance penile hemodynamics with an intention of outlining the fundamental mechanisms by which this therapy may help manage ED.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 8 print issues and online access
$259.00 per year
only $32.38 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Lu Z, Lin G, Reed-Maldonado A, Wang C, Lee YC, Lue TF. Low-intensity extracorporeal shock wave treatment improves erectile function: a systematic review and meta-analysis. Eur Urol. 2017;71:223–33.
Chung E, Wang J. A state-of-art review of low intensity extracorporeal shock wave therapy and lithotripter machines for the treatment of erectile dysfunction. Expert Rev Med Devices. 2017;14:929–34.
Xu JK, Chen HJ, Li XD, et al. Optimal intensity shock wave promotes the adhesion and migration of rat osteoblasts via integrin beta1-mediated expression of phosphorylated focal adhesion kinase. J Biol Chem. 2012;287:26200–12.
Wang CJ. An overview of shock wave therapy in musculoskeletal disorders. Chang Gung Med J. 2003;26:220–32.
Kertzman P, Csaszar NBM, Furia JP, Schmitz C. Radial extracorporeal shock wave therapy is efficient and safe in the treatment of fracture nonunions of superficial bones: a retrospective case series. J Orthop Surg. 2017;12:164.
Li W, Pan Y, Yang Q, Guo ZG, Yue Q, Meng QG. Extracorporeal shockwave therapy for the treatment of knee osteoarthritis: a retrospective study. Medicine. 2018;97:e11418.
d’Agostino MC, Craig K, Tibalt E, Respizzi S. Shock wave as biological therapeutic tool: From mechanical stimulation to recovery and healing, through mechanotransduction. Int J Surg. 2015;24:147–53.
Ohl SW, Klaseboer E, Khoo BC. Bubbles with shock waves and ultrasound: a review. Interface Focus. 2015;5:20150019
Rassweiler JJ, Knoll T, Kohrmann KU, et al. Shock wave technology and application: an update. Eur Urol. 2011;59:784–96.
Hazan-Molina H, Reznick AZ, Kaufman H, Aizenbud D. Periodontal cytokines profile under orthodontic force and extracorporeal shock wave stimuli in a rat model. J Periodontal Res. 2015;50:389–96.
Becker M, Goetzenich A, Roehl AB, et al. Myocardial effects of local shock wave therapy in a Langendorff model. Ultrasonics. 2014;54:131–6.
Yang P, Guo T, Wang W, et al. Randomized and double-blind controlled clinical trial of extracorporeal cardiac shock wave therapy for coronary heart disease. Heart Vessels. 2013;28:284–91.
Hayashi D, Kawakami K, Ito K, et al. Low-energy extracorporeal shock wave therapy enhances skin wound healing in diabetic mice: a critical role of endothelial nitric oxide synthase. Wound Repair Regen. 2012;20:887–95.
Cooper B, Bachoo P. Extracorporeal shock wave therapy for the healing and management of venous leg ulcers. Cochrane Database Syst Rev. 2018;6:CD011842.
Fojecki GL, Tiessen S, Osther PJ. Extracorporeal shock wave therapy (ESWT) in urology: a systematic review of outcome in Peyronie’s disease, erectile dysfunction and chronic pelvic pain. World J Urol. 2017;35:1–9.
Yafi FA, Pinsky MR, Sangkum P, Hellstrom WJ. Therapeutic advances in the treatment of Peyronie’s disease. Andrology . 2015;3:650–60.
Hatzichristodoulou G, Meisner C, Gschwend JE, Stenzl A, Lahme S. Extracorporeal shock wave therapy in Peyronie’s disease: results of a placebo-controlled, prospective, randomized, single-blind study. J Sex Med. 2013;10:2815–21.
Abu-Ghanem Y, Kitrey ND, Gruenwald I, Appel B, Vardi Y. Penile low-intensity shock wave therapy: a promising novel modality for erectile dysfunction. Korean J Urol. 2014;55:295–9.
Clavijo RI, Kohn TP, Kohn JR, Ramasamy R. Effects of low-intensity extracorporeal shockwave therapy on erectile dysfunction: a systematic review and meta-analysis. J Sex Med. 2017;14:27–35.
Vardi Y, Appel B, Jacob G, Massarwi O, Gruenwald I. Can low-intensity extracorporeal shockwave therapy improve erectile function? A 6-month follow-up pilot study in patients with organic erectile dysfunction. Eur Urol. 2010;58:243–8.
Burnett AL, Nehra A, Breau RH, et al. Erectile dysfunction: AUA guideline. J Urol. 2018;200:633–641.
Lin G, Reed-Maldonado AB, Wang B, et al. In situ activation of penile progenitor cells with low-intensity extracorporeal shockwave therapy. J Sex Med. 2017;14:493–501.
Weihs AM, Fuchs C, Teuschl AH, et al. Shock wave treatment enhances cell proliferation and improves wound healing by ATP release-coupled extracellular signal-regulated kinase (ERK) activation. J Biol Chem. 2014;289:27090–104.
Xin ZC, Xu YD, Lin G, Lue TF, Guo YL. Recruiting endogenous stem cells: a novel therapeutic approach for erectile dysfunction. Asian J Androl. 2016;18:10–5.
Shan HT, Zhang HB, Chen WT, et al. Combination of low-energy shock-wave therapy and bone marrow mesenchymal stem cell transplantation to improve the erectile function of diabetic rats. Asian J Androl. 2017;19:26–33.
Zhang J, Kang N, Yu X, Ma Y, Pang X. Radial extracorporeal shock wave therapy enhances the proliferation and differentiation of neural stem cells by notch, PI3K/AKT, and Wnt/beta-catenin signaling. Sci Rep. 2017;7:15321.
Wang B, Zhou J, Banie L, et al. Low-intensity extracorporeal shock wave therapy promotes myogenesis through PERK/ATF4 pathway. Neurourol Urodyn. 2018;37:699–707.
Zou ZJ, Liang JY, Liu ZH, Gao R, Lu YP. Low-intensity extracorporeal shock wave therapy for erectile dysfunction after radical prostatectomy: a review of preclinical studies. Int J Impot Res. 2018;30:1–7.
Dietz-Laursonn K, Beckmann R, Ginter S, Radermacher K, de la Fuente M. In-vitro cell treatment with focused shockwaves-influence of the experimental setup on the sound field and biological reaction. J Ther Ultrasound. 2016;4:10.
Jaalouk DE, Lammerding J. Mechanotransduction gone awry. Nat Rev Mol Cell Biol. 2009;10:63–73.
Huang C, Holfeld J, Schaden W, Orgill D, Ogawa R. Mechanotherapy: revisiting physical therapy and recruiting mechanobiology for a new era in medicine. Trends Mol Med. 2013;19:555–64.
Guan JL. Focal adhesion kinase in integrin signaling. Matrix Biol. 1997;16:195–200.
Guan JL, Shalloway D. Regulation of focal adhesion-associated protein tyrosine kinase by both cellular adhesion and oncogenic transformation. Nature. 1992;358:690–2.
Kurenova E, Xu LH, Yang X, et al. Focal adhesion kinase suppresses apoptosis by binding to the death domain of receptor-interacting protein. Mol Cell Biol. 2004;24:4361–71.
Owen JD, Ruest PJ, Fry DW, Hanks SK. Induced focal adhesion kinase (FAK) expression in FAK-null cells enhances cell spreading and migration requiring both auto- and activation loop phosphorylation sites and inhibits adhesion-dependent tyrosine phosphorylation of Pyk2. Mol Cell Biol. 1999;19:4806–18.
Sieg DJ, Hauck CR, Schlaepfer DD. Required role of focal adhesion kinase (FAK) for integrin-stimulated cell migration. J Cell Sci. 1999;112:2677–91.
Lee FY, Zhen YY, Yuen CM, et al. The mTOR-FAK mechanotransduction signaling axis for focal adhesion maturation and cell proliferation. Am J Transl Res. 2017;9:1603–17.
Hatanaka K, Ito K, Shindo T, et al. Molecular mechanisms of the angiogenic effects of low-energy shock wave therapy: roles of mechanotransduction. Am J Physiol Cell Physiol. 2016;311:C378–85.
Holfeld J, Tepekoylu C, Blunder S, et al. Low energy shock wave therapy induces angiogenesis in acute hind-limb ischemia via VEGF receptor 2 phosphorylation. PLoS One. 2014;9:e103982.
Lie DC, Colamarino SA, Song HJ, et al. Wnt signalling regulates adult hippocampal neurogenesis. Nature. 2005;437:1370–5.
Thrasivoulou C, Millar M, Ahmed A. Activation of intracellular calcium by multiple Wnt ligands and translocation of beta-catenin into the nucleus: a convergent model of Wnt/Ca2+and Wnt/beta-catenin pathways. J Biol Chem. 2013;288:35651–9.
Malbon CC. Frizzleds: new members of the superfamily of G-protein-coupled receptors. Front Biosci. 2004;9:1048–58.
Penton A, Wodarz A, Nusse R. A mutational analysis of dishevelled in Drosophila defines novel domains in the dishevelled protein as well as novel suppressing alleles of axin. Genetics. 2002;161:747–62.
Pai SG, Carneiro BA, Mota JM, et al. Wnt/beta-catenin pathway: modulating anticancer immune response. J Hematol Oncol. 2017;10:101.
Chiurillo MA. Role of the Wnt/beta-catenin pathway in gastric cancer: an in-depth literature review. World J Exp Med. 2015;5:84–102.
Mattyasovszky SG, Langendorf EK, Ritz U, et al. Exposure to radial extracorporeal shock waves modulates viability and gene expression of human skeletal muscle cells: a controlled in vitro study. J Orthop Surg. 2018;13:75.
Kang N, Zhang J, Yu X, Ma Y. Radial extracorporeal shock wave therapy improves cerebral blood flow and neurological function in a rat model of cerebral ischemia. Am J Transl Res. 2017;9:2000–12.
Yang SY, Wei FL, Hu LH, Wang CL. PERK-eIF2alpha-ATF4 pathway mediated by endoplasmic reticulum stress response is involved in osteodifferentiation of human periodontal ligament cells under cyclic mechanical force. Cell Signal. 2016;28:880–6.
Wang B, Ning H, Reed-Maldonado AB, et al. Low-intensity extracorporeal shock wave therapy enhances brain-derived neurotrophic factor expression through PERK/ATF4 signaling pathway. Int J Mol Sci. 2017;18:e433.
Burnstock G. Purinergic signalling: its unpopular beginning, its acceptance and its exciting future. Bioessay. 2012;34:218–25.
Qi B, Yu T, Wang C, et al. Shock wave-induced ATP release from osteosarcoma U2OS cells promotes cellular uptake and cytotoxicity of methotrexate. J Exp Clin Cancer Res. 2016;35:161.
Kowianski P, Lietzau G, Czuba E, Waskow M, Steliga A, Morys J. BDNF: a key factor with multipotent impact on brain signaling and synaptic plasticity. Cell Mol Neurobiol. 2018;38:579–93.
Axten JM, Romeril SP, Shu A, et al. Discovery of GSK2656157: an optimized PERK inhibitor selected for preclinicaldevelopment. ACS Med Chem Lett. 2013;4:964–8.
Nakamura K, Martin KC, Jackson JK, Beppu K, Woo CW, Thiele CJ. Brain-derived neurotrophic factor activation of TrkB induces vascular endothelial growth factor expression via hypoxia-inducible factor-1alpha in neuroblastoma cells. Cancer Res. 2006;66:4249–55.
Lin CY, Hung SY, Chen HT, et al. Brain-derived neurotrophic factor increases vascular endothelial growth factor expression and enhances angiogenesis in human chondrosarcoma cells. Biochem Pharmacol. 2014;91:522–33.
Zhu GQ, Jeon SH, Bae WJ, et al. Efficient promotion of autophagy and angiogenesis using mesenchymal stem cell therapy enhanced by the low-energy shock waves in the treatment of erectile dysfunction. Stem Cells Int. 2018;2018:1302672.
Acknowledgements
This publication was supported by NIDDK of the National Institutes of Health under award number R56DK105097 and 1R01DK105097–01A1. It was also supported by Army, Navy, NIH, Air Force, VA and Health Affairs to support the AFIRM II effort, under Award number W81XWH-13–2–0052. Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense and do not necessarily represent the official views of the National Institutes of Health.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Liu, T., Shindel, A.W., Lin, G. et al. Cellular signaling pathways modulated by low-intensity extracorporeal shock wave therapy. Int J Impot Res 31, 170–176 (2019). https://doi.org/10.1038/s41443-019-0113-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41443-019-0113-3
This article is cited by
-
Unveiling the molecular Hallmarks of Peyronie’s disease: a comprehensive narrative review
International Journal of Impotence Research (2024)
-
Mechanisms of oxidative stress in interstitial cystitis/bladder pain syndrome
Nature Reviews Urology (2024)
-
The functional effects of Piezo channels in mesenchymal stem cells
Stem Cell Research & Therapy (2023)
-
News and future perspectives of non-surgical treatments for erectile dysfunction
International Journal of Impotence Research (2023)
-
Low-intensity shockwave therapy in Peyronie’s disease: long-term results from a prospective, randomized, sham-controlled trial
International Journal of Impotence Research (2022)