Shock wave therapy therefore could develop into a feasible alternative to stem cell therapy in regenerative medicine, in particular for ischemic heart and limb disease.
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.
Shock wave therapy (SWT) reportedly improves ventricular function in ischemic heart failure. Angiogenesis and inflammation modulatory effects were described. However, the mechanism remains largely unknown. We hypothesized that SWT modulates inflammation via toll-like receptor 3 (TLR3) through the release of cytosolic RNA. SWT was applied to human umbilical vein endothelial cells (HUVECs) with 250 impulses, 0.08 mJ/mm(2) and 3 Hz. Gene expression of TLR3, inflammatory genes and signalling molecules was analysed at different time points by real-time polymerase chain reaction. SWT showed activation of HUVECs: enhanced expression of TLR3 and of the transporter protein for nucleic acids cyclophilin B, of pro-inflammatory cytokines cyclophilin A and interleukin-6 and of anti-inflammatory interleukin-10. No changes were found in the expression of vascular endothelial cell adhesion molecule. SWT modulates inflammation via the TLR3 pathway. The interaction between interleukin (IL)-6 and IL-10 in TLR3 stimulation can be schematically seen as a three-phase regulation over time.
ObjectivesLow energy shock waves have been shown to induce angiogenesis, improve left ventricular ejection fraction and decrease angina symptoms in patients suffering from chronic ischemic heart disease. Whether there is as well an effect in acute ischemia was not yet investigated.MethodsHind-limb ischemia was induced in 10–12 weeks old male C57/Bl6 wild-type mice by excision of the left femoral artery. Animals were randomly divided in a treatment group (SWT, 300 shock waves at 0.1 mJ/mm2, 5 Hz) and untreated controls (CTR), n = 10 per group. The treatment group received shock wave therapy immediately after surgery.ResultsHigher gene expression and protein levels of angiogenic factors VEGF-A and PlGF, as well as their receptors Flt-1 and KDR have been found. This resulted in significantly more vessels per high-power field in SWT compared to controls. Improvement of blood perfusion in treatment animals was confirmed by laser Doppler perfusion imaging. Receptor tyrosine kinase profiler revealed significant phosphorylation of VEGF receptor 2 as an underlying mechanism of action. The effect of VEGF signaling was abolished upon incubation with a VEGFR2 inhibitor indicating that the effect is indeed VEGFR 2 dependent.ConclusionsLow energy shock wave treatment induces angiogenesis in acute ischemia via VEGF receptor 2 stimulation and shows the same promising effects as known from chronic myocardial ischemia. It may therefore develop as an adjunct to the treatment armentarium of acute muscle ischemia in limbs and myocardium.
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