Toll-like receptor 3 signalling mediates angiogenic response upon shock wave treatment of ischaemic muscle

Holfeld, Johannes; Tepeköylü, Can; Reissig, Christin; Lobenwein, Daniela; Scheller, Bertram; Kirchmair, Elke; Kozaryn, Radoslaw; Albrecht-Schgoer, Karin; Krapf, Christoph; Zins, Karin; Urbschat, Anja; Zacharowski, Kai; Grimm, Michael; Kirchmair, Rudolf; Paulus, Patrick

doi:10.1093/cvr/cvv272

Cited by 52 publications

(50 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In ischemic muscle, we had identified the effect of shock waves as TLR3 dependent. 17 In the current study, we were able to confirm this mechanism of action as being involved in spinal cord tissue. The effect of neuronal protection was almost completely abolished in TLR3-knockout mice, indicating the pivotal role of TLR3 signaling on SWT.…”

Section: Neuronal Protection Is Tlr3 Dependentsupporting

confidence: 66%

“…16 In previous work, we showed that shock wave therapy (SWT), a relatively new treatment approach, mediates regeneration of ischemic muscle via TLR3 signaling and simultaneously causes TLR4 downregulation. 17 TLR3 is the only TLR without signaling via myeloid differentiation primary response gene (MyD88). It is mediated via the adaptor molecule TIR-domain-containing adapter-inducing interferon-b (TRIF), and the transcription factor IRF3, which finally initiates transcription of interferons and interferon-induced genes.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Shock Wave Treatment Protects From Neuronal Degeneration via a Toll‐Like Receptor 3 Dependent Mechanism: Implications of a First‐Ever Causal Treatment for Ischemic Spinal Cord Injury

Lobenwein

Tepeköylü

Kozaryn

et al. 2015

JAHA

Self Cite

View full text Add to dashboard Cite

BackgroundParaplegia following spinal cord ischemia represents a devastating complication of both aortic surgery and endovascular aortic repair. Shock wave treatment was shown to induce angiogenesis and regeneration in ischemic tissue by modulation of early inflammatory response via Toll‐like receptor (TLR) 3 signaling. In preclinical and clinical studies, shock wave treatment had a favorable effect on ischemic myocardium. We hypothesized that shock wave treatment also may have a beneficial effect on spinal cord ischemia.Methods and ResultsA spinal cord ischemia model in mice and spinal slice cultures ex vivo were performed. Treatment groups received immediate shock wave therapy, which resulted in decreased neuronal degeneration and improved motor function. In spinal slice cultures, the activation of TLR3 could be observed. Shock wave effects were abolished in spinal slice cultures from TLR3−/− mice, whereas the effect was still present in TLR4−/− mice. TLR4 protein was found to be downregulated parallel to TLR3 signaling. Shock wave–treated animals showed significantly better functional outcome and survival. The protective effect on neurons could be reproduced in human spinal slices.ConclusionsShock wave treatment protects from neuronal degeneration via TLR3 signaling and subsequent TLR4 downregulation. Consequently, it represents a promising treatment option for the devastating complication of spinal cord ischemia after aortic repair.

show abstract

Section: Neuronal Protection Is Tlr3 Dependentsupporting

confidence: 66%

mentioning

confidence: 99%

Shock Wave Treatment Protects From Neuronal Degeneration via a Toll‐Like Receptor 3 Dependent Mechanism: Implications of a First‐Ever Causal Treatment for Ischemic Spinal Cord Injury

Lobenwein

Tepeköylü

Kozaryn

et al. 2015

JAHA

Self Cite

View full text Add to dashboard Cite

show abstract

“…Therefore, the “mechanical model” of urological lithotripsy has been substituted by a “biological” one, also supported by the current knowledge in mechanobiology, an emerging multidisciplinary field of science that investigates how physical forces and changes in cell/tissue mechanics can influence the tissue development, physiology and diseases. Although some details are still under investigation, it is known that ESWT are able to relieve pain, reduce inflammation, and induce neoangiogenesis and stem cell activities, thus improving tissue regeneration and healing [58, 60]. …”

Section: Extracorporeal Shock Wave Therapymentioning

confidence: 99%

Mesenchymal stem cells as therapeutic target of biophysical stimulation for the treatment of musculoskeletal disorders

et al. 2016

View full text Add to dashboard Cite

BackgroundMusculoskeletal disorders are regarded as a major cause of worldwide morbidity and disability, and they result in huge costs for national health care systems. Traditional therapies frequently turned out to be poorly effective in treating bone, cartilage, and tendon disorders or joint degeneration. As a consequence, the development of novel biological therapies that can treat more effectively these conditions should be the highest priority in regenerative medicine.Main body of the abstractMesenchymal stem cells (MSCs) represent one of the most promising tools in musculoskeletal tissue regenerative medicine, thanks to their proliferation and differentiation potential and their immunomodulatory and trophic ability. Indeed, MSC-based approaches have been proposed for the treatment of almost all orthopedic conditions, starting from different cell sources, alone or in combination with scaffolds and growth factors, and in one-step or two-step procedures. While all these approaches would require cell harvesting and transplantation, the possibility to stimulate the endogenous MSCs to enhance their tissue homeostasis activity represents a less-invasive and cost-effective therapeutic strategy. Nowadays, the role of tissue-specific resident stem cells as possible therapeutic target in degenerative pathologies is underinvestigated. Biophysical stimulations, and in particular extracorporeal shock waves treatment and pulsed electromagnetic fields, are able to induce proliferation and support differentiation of MSCs from different origins and affect their paracrine production of growth factors and cytokines.Short conclusionsThe present review reports the attempts to exploit the resident stem cell potential in musculoskeletal pathologies, highlighting the role of MSCs as therapeutic target of currently applied biophysical treatments.

show abstract

“…To confirm the potential intracellular signaling pathways, in vivo studies with genetically modified animals (e.g., caveolin-1 knockout mice) may be useful. Third, it was previously reported that vascular endothelial cadherin, platelet endothelial cell adhesion molecule-1, and Toll-like receptor 3 may also be involved in the effects of SW therapy (13,15). Thus it is possible that these molecules interact with caveolin-1 and ␤ 1 -integrin.…”

Section: Discussionmentioning

confidence: 96%

Molecular mechanisms of the angiogenic effects of low-energy shock wave therapy: roles of mechanotransduction

Hatanaka

Ito

Shindo

et al. 2016

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

H. Molecular mechanisms of the angiogenic effects of low-energy shock wave therapy: roles of mechanotransduction. Am J Physiol Cell Physiol 311: C378 -C385, 2016. First published July 13, 2016; doi:10.1152/ajpcell.00152.2016.-We have previously demonstrated that low-energy extracorporeal cardiac shock wave (SW) therapy improves myocardial ischemia through enhanced myocardial angiogenesis in a porcine model of chronic myocardial ischemia and in patients with refractory angina pectoris. However, the detailed molecular mechanisms for the SW-induced angiogenesis remain unclear. In this study, we thus examined the effects of SW irradiation on intracellular signaling pathways in vitro. Cultured human umbilical vein endothelial cells (HUVECs) were treated with 800 shots of low-energy SW (1 Hz at an energy level of 0.03 mJ/mm 2 ). The SW therapy significantly upregulated mRNA expression and protein levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS). The SW therapy also enhanced phosphorylation of extracellular signal-regulated kinase 1/2 (Erk1/2) and Akt. Furthermore, the SW therapy enhanced phosphorylation of caveolin-1 and the expression of HUTS-4 that represents ␤1-integrin activity. These results suggest that caveolin-1 and ␤1-integrin are involved in the SW-induced activation of angiogenic signaling pathways. To further examine the signaling pathways involved in the SW-induced angiogenesis, HUVECs were transfected with siRNA of either ␤ 1-integrin or caveolin-1. Knockdown of either caveolin-1 or ␤ 1-integrin suppressed the SW-induced phosphorylation of Erk1/2 and Akt and upregulation of VEGF and eNOS. Knockdown of either caveolin-1 or ␤1-integrin also suppressed SW-induced enhancement of HUVEC migration in scratch assay. These results suggest that activation of mechanosensors on cell membranes, such as caveolin-1 and ␤1-integrin, and subsequent phosphorylation of Erk and Akt may play pivotal roles in the SW-induced angiogenesis. shock wave; mechanotransduction; angiogenesis; caveolin-1; ␤1-integrin SHOCK WAVES (SW) have been clinically introduced for lithotripsy since the 1980s; urinary stones are broken up by highenergy SW (7). The waveform of an SW is similar to that of a blast wave, which is composed of discontinuous compression of leading shock propagating with supersonic speed, subsequent rarefaction, and negative pressure (27). Over the past 20 years, low-energy SW therapy has also been put into clinical application (3,17). We have previously demonstrated that low-energy SW (about 10% of the energy used for urolithotripsy treatment) significantly upregulated vascular endothelial growth factor (VEGF) in human umbilical vein endothelial cells (HUVECs) (25). Low-energy SW therapy has also been reported to enhance nitric oxide (NO) production via activation of endothelial NO synthase (eNOS) in vitro (23,24). We have demonstrated that extracorporeal low-energy cardiac SW therapy enhances angiogenesis and contractile function in a porcine model of chronic myocardial isc...

show abstract

Toll-like receptor 3 signalling mediates angiogenic response upon shock wave treatment of ischaemic muscle

Abstract: Our data reveal a central role of the innate immune system, namely Toll-like receptor 3, to mediate angiogenesis upon release of cytoplasmic RNAs by mechanotransduction of SWT.

Cited by 52 publications

References 34 publications

Shock Wave Treatment Protects From Neuronal Degeneration via a Toll‐Like Receptor 3 Dependent Mechanism: Implications of a First‐Ever Causal Treatment for Ischemic Spinal Cord Injury

Shock Wave Treatment Protects From Neuronal Degeneration via a Toll‐Like Receptor 3 Dependent Mechanism: Implications of a First‐Ever Causal Treatment for Ischemic Spinal Cord Injury

Mesenchymal stem cells as therapeutic target of biophysical stimulation for the treatment of musculoskeletal disorders

Molecular mechanisms of the angiogenic effects of low-energy shock wave therapy: roles of mechanotransduction

Contact Info

Product

Resources

About